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BCH B – Flashcard

Candace Young

16 October 2020

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Hemoglobin

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A four-subunit protein found in red blood cells that binds oxygen. Each subunit contains a heme group, a large multi-ring molecule with an iron atom at its center. One hemoglobin molecule can bind four oxygen molecules in a cooperative manner

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Molecular structure of hemoglobin

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1. Quaternary structure; 2 alpha chains (polypeptides), 2 non-alpha chains 2. Predominantly alpha helical 3. Four heme groups; one per subunit, planar porphyrin ring system

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Heme

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The iron-containing nonprotein fraction of hemoglobin. Planar porphyrin ring system with ferrous iron (Fe2+) bound at center

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What state must iron be in?

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Ferrous ion state or Fe2+. It is crucial that Fe2+ state because if it is at the Fe3+ (ferrite state) oxygen cannot bind

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Free heme vs protein-bound (ligand binding)

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Another molecule that can bind to the Fe2+ is carbon monoxide. CO can bind 20000x more efficiently that O2. Another protein-bound molecule can sterically hinder CO and reduce the effectiveness to only 200x when compared to O2

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Myoglobin and alpha & beta globins share _____ primary sequence identities

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Few. Very different at the primary structure

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Secondary structure is _________ between alpha & beta globins

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Similar

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Tertiary structure of hemoglobin is shaped very _____ to myoglobin

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Similarly

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When does hemoglobin begin to look much more different than myoglobin?

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Quaternary (4th) structure

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What is the shape of the oxygen-binding curve of myoglobin?

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Hyperbolic

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What is the shape of the oxygen-binding curve of hemoglobin?

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Sigmoidal or "S-shaped" curve. Binding affinity of each heme group changes as the amount of oxygen is bound to the hemoglobin

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Derivation of Hb oxygen-binding curve

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1. In high O2 conditions (lungs), Hb is in state to bind O2 2. In low O2 conditions (tissues), Hb is in state to release O2 We get this sigmoidal curve from the transition of the low and high-affinity curves

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T state

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Tight/taut state is a low-affinity or deoxyHb (w/o oxygen). Is more open (looks like a doughnut) with salt bridges formed

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R state

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Relaxed state is a high-affinity state with oxygen

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Salt bridges

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Interactions with positive and negative charges. Salt bridges stabilize the structure of each polypeptide which does not favor the oxygen binding

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Salt bridges stabilize what state?

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T State. O2 binding disrupts salt bridges

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Transition from T to R state

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There are many transition states between the T and R states of hemoglobin

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Biochemical basis of Bohr Effect

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In periphery we have a lower pH (more acidic). HHb+ + O2 HbO2 + H+

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What contributes to salt bridge formation and favors T (deoxy) state

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Protonation

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What decreases hemoglobin's affinity for O2?

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BPG

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BPG

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Byproduct of glycolysis. Without BPG the hemoglobin begins to look more like myoglobin which helps shape the hemoglobin sigmoidal curve. More BPG shifts the curve to the right (right-shift) which can release more oxygen. Binding of BPG stabilizes T (deoxy) state; likes to bind to the "middle of the doughnut" to stabilize the T-state

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Which of the following would be true for an acidemic patient? A. Their hemoglobin has an increased affinity for oxygen; B. Their hemoglobin has a decreased affinity for BPG; C. Their oxygen dissociation curve is shifted to the right; D. Their hemoglobin is more likely to be in the relaxed state

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C. Their oxygen dissociation is shifted to the right. Correct statements: A. Their hemoglobin has a decreased affinity for oxygen B. Their hemoglobin has an increased affinity for BPG D. Their hemoglobin is more likely to be in the T state

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Right-shift favors . . .

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Increased H+, lower pH, decreased affinity for O2 - more like T-state

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Left-shift favors . . .

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Decreased H+, higher pH, increased affinity for O2 - more like R-state

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Chromosome 16

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Has alpha like genes. Genes on the left are expressed earlier and developmentally expressed later

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Chromosome 11

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Has non-alpha like genes. Genes on the left are expressed earlier and developmentally expressed later

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alpha2 and alpha1 duplication

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1. Differ only in promoters 2. Alpha2 promoter is stronger 3. Alpha2:Alpha1 expression is 2:1

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Mutation in what alpha gene is more severe?

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Alpha2

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Ggamma and Agamma duplication

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1. Gly and Ala substitution 2. Functionality, performance, expression level are identical 3. No biological or disease significance

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Developmental expression of heme genes

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Please see picture

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Structure of HbA

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Alpha2Beta2. Percentage of normal hemolysate (individuals more than 8 months old) = 92.5%

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Structure of HbA2

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Alpha2Delta2. Percentage of normal hemolysate = 2.5%

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Structure of HbA1c

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Alpha2(Beta-N-glucose)2. Percentage of normal hemolysate = 4.0%

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What is HbA1c increased in? Decreased in?

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Increased in DM. Decreased in hemolytic anemia

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Structure of HbF

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Alpha2Gamma2. Percentage of normal hemolysate = less than 1%

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What is HbF increased in?

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Increased in Beta Thalassemia

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Structure of HbH

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Beta4. Percentage of normal hemolysate = 0%

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What is HbH increased in?

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Increased in Alpha Thalassemia

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Structure of Hb Bart's

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Gamma4. Percentage of normal hemolysate = 0%

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What is Hb Bart's increased in?

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Increased in Alpha Thalassemia

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Oxygen affinity of HbF (Alpha2Gamma2) vs. HbA (Alpha2Beta2)

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1. Gamma chain vs. Beta chain - 72% identical 2. One important difference is gamma chain has a Ser instead of His 3. Binds BPG with reduced affinity 4. Affinity for O2 is increased and HbF (fetal version) can take O2 from HbA (from mother)

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Thalassemias

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Single most common defect - decreased production of a globin chain - "right protein, wrong amount"

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Hemoglobinopathies

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"Wrong protein, right amount"

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Alpha Thalassemias

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1. Decreased Alpha, surplus Beta (and Gamma) 2. Principal etiology is complete deletion of an alpha gene 3. More common, less dangerous Less dangerous because there are two alpha genes. HbH and HbBarts tend to resemble R-state and are unstable. Complete loss of alpha is fatal in the fetal stage

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Fate of surpluse Beta and Gamma chains (Alpha Thalassemias)

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Form soluble tetramers Beta4 (HbH) or Gamma4 (Hb Bart's) - unstable 1. Can precipitate, forming insoluble inclusions (Heinz bodies) 2. High affinity, no cooperativity, poorly release O2 in tissue, P50 = ~2 mmHg

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Beta Thalassemias

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1. Decreased Beta, surplus Alpha 2. Principal etiology is small substitution or deletion mutation of a Beta gene 3. Less common, more dangerous More dangerous because there is only a single Beta gene. Beta Thalassemias would be more apparent post-natal (after birth)

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Fate of surplus Alpha chains (Beta Thalassemias)

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Cannot tetramerize - polymerize into tactoid structures (insoluble aggregates) which distort the erythrocyte and stress the membrane - severe hemolysis; extreme cases must be treated by transfusion therapy

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Hemoglobin S - Beta-globin defect (Hemoglobinopathies)

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1. Substitution of Valine and Glutamate at the 6th position 2. Creates a hydrophobic "sticky patch" 3. Complementary sticky patch is exposed in deoxy state 4. Sticky patches interact to form fibrous aggregates (tactoids) at low PO2 5. Hemolytic and vaso-occlusive

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Hemoglobin Electrophoresis

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Please see picture

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Potential therapies for hemoglobin-related diseases

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1. Bone marrow transplant (cure) 2. Blood transfusions (and possibly iron chelation therapy) 3. Hydroxyurea treatment to stimulate synthesis of Gamma chains (and HbF) - for Beta globin diseases

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How might synthesis of Gamma chains help a sickle cell patient?

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Formation of HbF helps prevent HbS formation

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Characteristics of benign tumors

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1. Benign tumors are localized and encapsulated (not invasive) 2. Benign tumor cells are more differentiated than cells in malignant tumors; very easy to tell benign tumor cells from normal tissue

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Characteristics of malignant tumors (cancers)

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Invasive and/or metastatic; very difficult to find border of malignant tumors with normal tissue. Locally invasive tumors are also cancers

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Note on invasive tumors and surgery

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Invasive, invade into surrounding normal tissues, making boarders between cancer and normal tissue difficult to define. That is also the reason that sometime surgeons thought they removed all the tumor cells, but the tumor grew back later on or even spread to other places. Thus, in most cases, surgeons try to remove not onl y the tumor but also tumor's surrounding tissues as much as possible. Locally invasive tumors are cancers. All cancers are invasive but not all cancers are metastatic, brain cancer is usually nonmetastatic. Malignant tumors usually start as benign tumors, they become malignant only after they become invasive

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What is cancer?

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A term for diseases in which abnormal cells divide without control and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymph systems (metastasis). An invasive growth or tumor that is likely to metastasize to other sites without surgery or treatment. 1. Uncontrolled growth and spread 2. Invasive growth that is likely to spread

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Metastasis

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1. Is the spread of cancer from one organ or part to another NON-ADJACENT organ or part. 2. Cancer cells can break away, leak, or spill from a primary tumor, enter LYMPHATIC AND BLOOD VESSELS, circulate through the bloodstream, and be deposited within normal tissue elsewhere in the body 3. Is a complex MULTI-STEP process, usually at the LATE STAGE of cancer 4. Involves malignant cells break away, attach to and degrade proteins that make up the surrounding EXTRACELLULAR MATRIX (ECM), ESCAPE, AND ESTABLISH SECONDARY TUMORS

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Stages in tumor growth and metastasis

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1. A single modified cell appears in a tissue 2. Division of the single modified cell. Tumor is still BENIGN AT THIS STAGE; As long as it is not invading its surrounding normal tissues, the tumor is still considered as benign 3. Invasion of the basal lamina by the tumor cells (may accompany with angiogenesis) 4. The tumor cells spread into blood vessels that will distribute cancer cells to other sites

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Oncogenesis

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A multi-step, dynamic and evolutionary process, with each step corresponding to a different genetic mutation(s) in different genes

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Angiogenesis

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Is the formation of new blood vessels in and around tumor. The purpose of angiogenesis is for tumor to obtain more nutrients for faster growth and proliferation

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Carcinomas (types of cancers)

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Cancers of epithelial cells (~90%)

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Sarcomas (types of cancers)

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Cancers of the supporting tissues such as bone, cartilage, fat, connective tissue, and muscle

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Leukemias (types of cancers)

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Cancers of hemopoietic cells (in bone marrow)

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Lymphomas and myelomas (types of cancers)

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Cancers that arise in the immune system

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Central nervous system cancers (types of cancers)

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Cancers that begin in the tissue of the bran and spinal cord

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Six hallmarks of cancer in 2000

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1. Sustaining proliferative signaling 2. Evading growth suppressors 3. Activating invasion and metastasis 4. Enabling replicative immortality 5. Inducing angiogenesis 6. Resisting cell death

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Sustaining proliferative signaling (hallmarks of cancer in 2000)

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Oncogenic signaling

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Evading growth suppressors (hallmarks of cancer in 2000)

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Loss of tumor suppression

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Activating invasion and metastasis (hallmarks of cancer in 2000)

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Invasion and metastasis

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Enabling replicative immortality (hallmarks of cancer in 2000)

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Telomere and telomerase

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Inducing angiogenesis (hallmarks of cancer in 2000)

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New blood vessel formation

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Resisting cell death (hallmarks of cancer in 2000)

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Resistance of apoptosis

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Four emerging hallmarks of cancer since 2010

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1. Avoid immune destruction 2. Tumor-promoting inflammation 3. Genome instability and mutation 4. Deregulating cellular energetics

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Avoiding immune destruction (hallmarks of cancer since 2010)

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Immuno-evasion

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Tumor-promoting inflammation (hallmarks of cancer since 2010)

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Inflammation (enabling characteristics)

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Genome instability an mutation (hallmarks of cancer since 2010)

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Cancer genomics (enabling characteristics)

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Deregulating cellular energetics (hallmarks of cancer since 2010)

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Cancer metabolism

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Cancer rates are genetically, environmentally, and culturally influenced

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You will find that different countries have different rates for different cancers and some cancers with low occurrence rates may be the cancer of highest occurrence rate in other countries. Skin cancer for Australia (sun and UV exposure), liver cancer in China due to large population of people infected with hepatitis B, Colon cancer in the US due to high consumption of meat and red meat

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In addition to genetics, what other factors play significant roles in oncogenesis?

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Environment and culture (diet in this case). Take Japanese people and Americans as examples. Japanese people living in Japan have very low level of colon cancer. However, if they immigrate to the US, their colon cancer rate increases many fold, close to the rate of Americans. On the other hand, Japanese people living in Japan have very high rate of stomach cancer. Once they come and live in the US, their stomach cancer rate is significantly decreased. These changes are attributed to the diet changes. Thus, environmental and cultural factors either contribute or reduce cancer occurrence rates

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Diet's role on certain cancers

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Diet and fat/calorie consumption play significant role in certain types of cancer (breast cancer is another example). For example, Americans eat significantly more meat than Japanese people and meat consumption has been well correlated to colon cancer rates. The higher the meat consumption rate, the higher the colon cancer rates. Breast cancer rates are also correlated with caloric intake

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Cancer lag time

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1. There is a good correlation between smoking and lung cancer 2. There is a delay (lag time) of ~20-30 years between smoking and lung cancer

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How many signaling pathways and processes are found to be mutated and disregulated in pancreatic caner? Mutations in more than how many genes are identified and involve?

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13 and 40 respectively. Similar results are also found in brain cancer, breast cancer, and colon cancer

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Key information from genomic studies of cancer

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1. Multiple genetic mutations are needed for cancer to develop 2. Different cancer requires (contains) different number of genetic (gene) mutations 3. Mutations in both tumor suppressor genes and proto-oncogenes are needed for cancer to develop

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What two types of cancers contain the most genetic mutations?

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Skin and lung cancer. Skin cancer and lung cancer can have more than mutations in more than 100 genes. This is not surprising because our skin and lung are exposed to most carcinogens . UV and air are the major causing factors

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Driver genes

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The most important gene mutation(s) at a given stage for oncogenesis to proceed. Drivers may be (usually are) different at different stages of oncogenesis

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Rider genes

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gene mutations that play a very small or no roles in oncogenesis at certain stages

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Key importance of driver and rider genes

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Drivers can change into riders and riders can change into drivers at different stages of oncogenesis. Try always to target drivers. It also means that the treatment need to change if drivers are changed in the cancer

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Effective anticancer therapies are those that target driver or rider genes?

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Driver genes

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The development an metastasis of human colorectal cancer and its genetic basis

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1. Loss of APC tumor suppressor gene 2. Activation of K-ras oncogene 3. Loss of DCC tumor suppressor gene 4. Loss of p53 tumor-suppressor gene 5. Other changes in genes whose products are involved in assisting metastasis; same cancer from different people may have different mutations in different sets of genes (or different sequence of mutations)

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Summary of the causes of cancer and oncogenic process

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1. By mutations in genes that are involved in various aspects (processes) of cell growth. 2. By oncogenes and mutations of tumor suppressor genes 3. Oncogenesis is a complex and multi-step evolving and dynamic process 4. Caused and maintained by genetic mutations and by altered cell metabolism (cancer metabolism)

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Cancer stem cell hypothesis

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Hypothesis: Tumors often originate from the transformation of normal stem cells, similar signaling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells include 'cancer stem cells' — rare cells with indefinite potential for self-renewal that drive tumorigenesis Observations: Cancer cells are fast replicating and usually less-differentiated, and immortal cells

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Cancer stem cell model

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Tumor cells are heterogeneous and only the cancer stem cell subset (CSC; yellow) has the ability to proliferate extensively and form new tumors. CSC model is well established

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Clonal evolution model

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Tumor cells are heterogeneous, but most cells can proliferate extensively and form new tumors

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Cancer stem cells (CSC)

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1. Cancers have cancer stem cells that are responsible for most of the cancer growth, metastasis, and drug resistance 2. Different cancers have different CSC (different cell surfacemarkers) 3. Different cancers have different percentage of CSC 4.. CSC has become a new therapeutic target in cancer treatment

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Proto-oncogenes

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NORMAL CELLULAR GENES that encode proteins involved in various aspects of cell growth and cell proliferation

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Oncogene

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Cancer-producing genes that are DERIVED FROM PROTO-ONCOGENES BY VARIOUS TYPES OF GENETIC MUTATIONS

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Proto-oncogenes and oncogenes are . . .

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Growth (cell proliferation) promoting genes

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Tumor suppressor genes are . . .

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Growth-suppressing (-decelerating or-inhibiting) genes

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What are the seven types of proteins that participate in controlling cell growth (any may be involved in oncogenesis)

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1. Growth factors 2. Growth factor receptors 3. Intracellular transducers 4. Transcription factors 5. Pro- or Anti-apoptosis proteins 6. Cell-cycle control proteins 7. DNA-repair proteins Cancer results from expression of mutant forms of these proteins

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Growth factors in cancer

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Normal growth factors (proteins) become oncogenic when they are OVER-EXPRESSED (over-produced)

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Name two important proto-oncogene receptor proteins

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1. HER2 2. EGF Both are a receptor tyrosine kinase (RTK)

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HER2

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The dimerized protein is constitutively active as a kinase - human breast cancer

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What is an effective treatment for one type of breast cancer involving HER2 receptor?

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Herceptin is a very effective drug treating one type of breast cancer in which Her2 receptor gene is mutated into Neu gene

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EGF receptor

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Dimerization of two receptor proteins in the absence of normal EGF-related ligand

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What types of cancers is EGFR involved in?

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EGFR is involved in many types of lung cancers, drugs targeting different EGFR mutations are effective in treating lung cancers

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Important of tyrosine kinases

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1. Mutated receptor tyrosine kinases and intracellular kinases are one type of key oncogenes 2. Many new targeted anticancer drugs target (inhibit) membrane bound tyrosine kinases or intracellular kinases - TKIs

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Ras

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Is a GTP-binding protein. Constitutively active Ras protein leads to uncontrolled cell growth and cancer

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Importance of Ras mutations (growth signal transducer)

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Ras mutations are found in more than 30% of all cancers. It is one of the most frequently mutated protooncogenes. Normal Ras can be in active and inactive states depending the cell needs. However, when Ras mutation occurs at aa position 12 or position 61, the Ras protein becomes active all the time - it is called constitutively active, transducing cell growth signal all the time, leading to cancer development

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What are two important proto-oncogene products following serum stimulation of quiescent 3T3 cells?

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1. c-Fos 2. c-Myc One of the earliest effects of growth factors is to induce transcription of c-Fos and c-Myc proto-oncogenes

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Fos and Myc

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Fos and Myc are two important transcription factors. Their activities are tightly controlled in normal cells and they are not in active state for long. However, in some cancer cells, you can find the Fos or Myc proteins are constitutively active, causing overexpression of genes involved in cell growth and lead to cancer

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The types of genetic mutations in the gene mutations include (3)?

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1. Point or deletion mutations 2. Gene amplification 3. Chromosome rearrangement

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A proto-oncogene can become an oncogene by?

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1. Mutations in the regulatory sequence; promoter 2. Mutations in the coding sequence in the gene 3. Chromosomal translocation 4. Gene amplification

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Philadelphia Chromosome

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Generated by the fusion or translocation of Ch 9 and Ch22, and the generation of a fusion gene of bcr and abl. Abl is a tyrosine kinase, the mutated bcr/able fusion protein becomes constitutively active, causing leukemia. Translocated chromosome in which part of chromosome 22 attaches to chromosome 9. Therefore, 22 becomes shorter and 9 becomes longer

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What type of cancer is a result of the Philadelphia chromosome?

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CML

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Tumor suppressor genes

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A tumor suppressor gene, or ANTI-ONCOGENE, is a gene that protects a cell from becoming cancerous. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to become cancerous, usually in combination with other genetic changes

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RB gene

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Is a tumor suppressor gene. Children wit hereditary retinoblastoma develop retinal tumors early in life and generally in both eyes. They inherit one mutant allele of the RB gene. Somatic mutation of the other allele coupled with oncogenic mutations in other genes leads to tumor development

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Two-hit hypothesis

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Some forms of hereditary cancer might be initiated when a cell in a person heterozygous for a germline mutation undergoes a second, somatic mutation in the other allele of the same gene, thus rendering the cell homozygous for loss of function mutations in a tumor-suppressor gene and giving rise to a tumor

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The two-hit origin of cancer theory applies only to what genes?

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Tumor suppressor genes, not oncogenes. It applies to the same tumor suppressor gene, not two different tumor suppressor genes

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p53 gene

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1. Tumor suppressor, transcription factor 2. Mutated or deleted in > 50% of all human cancers 3. May be the most important gene in human cancer 4. Cause of the genetic diseases Li-Fraumeni Syndrome

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The p53 gene is involved in (3)

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1. DNA damage repair 2. Cell cycle checkpoint control 3. Apoptosis

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Normal function of oncogenes (proto-oncogene)

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Cell growth-promoting (proto-oncogene)

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Normal function of tumor suppressor genes

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Cell growth-suppressing

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Consequences of mutation/genetic trait of oncogenes (from proto-oncogenes)

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GAIN of function. Genetic trait: Dominant (one allele), somatic mutations

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Consequences of mutation/genetic trait of tumor suppressor genes

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LOSS of function. Genetic trait: Recessive (both alleles) *but classified as dominant*, genetic inheritance

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G1 phase

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Rapid growth and centriole replication. 8-10 hours

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S phase

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Chromosome replication (DNA synthesis). 6-8 hours

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G2 phase

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Growth and final preparations for cell division. 4 to 6 hours

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Mitosis and Cytokinesis

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PMAT; Prophase, Metaphase, Anaphase, and Telophase followed by Cytokinesis

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G1/S checkpoint of the mitotic cell cycle is controlled by what two genes?

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1. p53 2. RB

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What proteins are used during the G2 phase of the mitotic cell cycle?

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Cyclins + CDKs; A group of proteins whose function is to regulate the progression of a cell through the cell cycle and whose concentrations rise and fall throughout the cell cycle

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Telomere

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Is a region of repetitive DNA at the end of a chromosome, which protects the end of the chromosome from destruction (similar to the plastic caps at the ends of shoelace)

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What replenishes telomeres after they are shortened during cell division?

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Telomerase

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Senescence

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Aging of the cell. As telomeres grow shorter, eventually cells reach the limit of their replicative capacity and progress into senescence

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What happens to the telomere in cancer cells?

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Cell would die when it telomere shortens and can no longer multiple; however telomere stays long in cancer cells. Telomere shortening can induce replicative senescence which blocks cell division. This mechanism prevents genomic instability and development of cancer in aged cells by limiting the number of cell divisions. Cancer cells which bypass this arrest become immortalized by telomere extension mostly due to the activation of telomerase, the enzyme responsible for synthesis of telomeres

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Compared to normal cells, cancer cells' telomerase activity is ________ and telomeres are _________ - two of the key reasons that cancer cells are immortalized

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Higher, longer respectively

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RNA and DNA viruses as cancer-producing agents

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1. Both RNA and DNA viruses can carry oncogenes 2. Both RNA and DNA viruses can induce cancer in animals and humans

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Oncogenes that function in viral replication cycle are characteristic of what type of virus?

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DNA virus. Oncogenes carried by RNA viruses do not have functions in viral replication cycle, whereas oncogenes carried by DNA viruses do participate in the replication cycle of viral hosts. Oncogenic mechanisms of the oncogenes carried by RNA viruses are very different from those of the oncogenes carried by DNA viruses

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Epstein-Barr virus can lead to what type of cancer?

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Burkitt's Lymphoma

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HPV can lead to what type of cancer?

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Cervical cancer

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Hepatitis B virus can lead to what type of cancer?

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Liver cancer

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Human T-cell lymphotrophic virus can lead to what type of cancer?

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Adult T-cell leukemia

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Kaposi's sarcoma-associated herpes virus can lead to what type of cancer?

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Kaposi's sarcoma

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Genomic structures of retroviruses

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1. There are two mechanisms for retroviruses to cause cancer - FAST OR SLOW tumor-forming 2. The genome of fast tumor-forming retrovirus contains an oncogene (onc)

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Fast tumor-forming retrovirus

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Contains an oncogene; onc

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Slow tumor-forming retrovirus

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Activation of the c-myc proto-oncogene by retroviral promoter and enhancer insertions

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HPV can cause cervical cancer, how?

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Once inside the cells of their host, HPV synthesizes a protein designated E7 - an oncogene product. E7 binds and inactivates p53 which causes E2F to start promoter "on" and cell begins mitosis

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Carry oncogenes

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Both DNA and RNA viruses

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Carry tumor suppressor genes

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Neither DNA or RNA viruses

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Carry oncogene as part of a normal viral genome

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Only DNA viruses

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Carry oncogene that has normal function in viral cycle

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Only DNA viruses

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How many mutations are needed for developing cancer?

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Incidence of human cancers increases markedly with age. Assuming the rate of mutation is roughly constant during a life-time, incidence of cancer would be independent of age if only one mutation is required for malignancy. Therefore, multiple mutations are required for cancer to form. We know that the mutation rate for DNA is quite constant in our life time. If only one mutation is needed for getting cancer, the cancer rate should be quite constant over time or getting a horizontal line on this graph. However, occurrence rates for all cancers get higher over age, indicating that multiple mutations are needed for getting cancer.

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Kinetics of tumor appearance in female transgenic mice carrying transgenes driven by the mouse mammary tumor virus (MMTV) breast-specific promoter

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Explanation: Females were studied because the hormonal stimulation of pregnancy activates expression of the MMTV-driven oncogenes. "Cooperativity" of oncogenic mutations and synergistic effects of oncogenes. Oncogenes work together to accelerate oncogenic process. Conclusion: I showed Ras oncogene and Myc oncogene. If there is only one mutation, either Ras or Myc in mice, it takes much longer for mice to develop cancer. However, if mice start with two mutated genes, both myc and Ras, they develop cancer at a much faster rate - this phenomenon is called cooperativity of oncogenes. One mutation leads to faster second mutation. Once first and second mutations occurs, subsequent mutations occur at faster and faster pace

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If therapies can be targeted against cancer stem cells, then the might be more effectively kill the cancer stem cells

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Because we did not know the existence of cancer stem cells before and our anticancer drugs or therapies were developed for targeting regular cancer cells, not cancer stem cells. Cancer stem cells are more resistant to these drugs or therapies. You can kill all the regular cancer cells, which is usually more than 90 to 95% of all cancer cells in a tumor nodule, and you will observe an initial shrinking of the tumor, only to witness the comeback of the tumor because cancer stem cells are resistant to the drug. If we target cancer stem cells, the efficacy of the drug should be higher

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Most tumor suppressors are involved in . . .

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1. Cell cycle regulation 2. DNA repair 3. Apoptosis Several times more tumor suppressor genes are found mutated than proto-oncogenes

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BRCA1 and BRCA2 are tumor suppressor genes involved in what type of familial cancer?

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Breast cancer

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Most familial cancers are consequences of what type of gene mutations?

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Tumor suppressor genes

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question

Hemoglobin

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Molecular structure of hemoglobin

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1. Quaternary structure; 2 alpha chains (polypeptides), 2 non-alpha chains 2. Predominantly alpha helical 3. Four heme groups; one per subunit, planar porphyrin ring system

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Heme

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The iron-containing nonprotein fraction of hemoglobin. Planar porphyrin ring system with ferrous iron (Fe2+) bound at center

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What state must iron be in?

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Ferrous ion state or Fe2+. It is crucial that Fe2+ state because if it is at the Fe3+ (ferrite state) oxygen cannot bind

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Free heme vs protein-bound (ligand binding)

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Myoglobin and alpha & beta globins share _____ primary sequence identities

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Few. Very different at the primary structure

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Secondary structure is _________ between alpha & beta globins

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Similar

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Tertiary structure of hemoglobin is shaped very _____ to myoglobin

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Similarly

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When does hemoglobin begin to look much more different than myoglobin?

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Quaternary (4th) structure

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What is the shape of the oxygen-binding curve of myoglobin?

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Hyperbolic

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What is the shape of the oxygen-binding curve of hemoglobin?

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Sigmoidal or "S-shaped" curve. Binding affinity of each heme group changes as the amount of oxygen is bound to the hemoglobin

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Derivation of Hb oxygen-binding curve

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T state

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Tight/taut state is a low-affinity or deoxyHb (w/o oxygen). Is more open (looks like a doughnut) with salt bridges formed

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R state

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Relaxed state is a high-affinity state with oxygen

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Salt bridges

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Interactions with positive and negative charges. Salt bridges stabilize the structure of each polypeptide which does not favor the oxygen binding

question

Salt bridges stabilize what state?

answer

T State. O2 binding disrupts salt bridges

question

Transition from T to R state

answer

There are many transition states between the T and R states of hemoglobin

question

Biochemical basis of Bohr Effect

answer

In periphery we have a lower pH (more acidic). HHb+ + O2 HbO2 + H+

question

What contributes to salt bridge formation and favors T (deoxy) state

answer

Protonation

question

What decreases hemoglobin's affinity for O2?

answer

BPG

question

BPG

answer

question

answer

question

Right-shift favors . . .

answer

Increased H+, lower pH, decreased affinity for O2 - more like T-state

question

Left-shift favors . . .

answer

Decreased H+, higher pH, increased affinity for O2 - more like R-state

question

Chromosome 16

answer

Has alpha like genes. Genes on the left are expressed earlier and developmentally expressed later

question

Chromosome 11

answer

Has non-alpha like genes. Genes on the left are expressed earlier and developmentally expressed later

question

alpha2 and alpha1 duplication

answer

1. Differ only in promoters 2. Alpha2 promoter is stronger 3. Alpha2:Alpha1 expression is 2:1

question

Mutation in what alpha gene is more severe?

answer

Alpha2

question

Ggamma and Agamma duplication

answer

1. Gly and Ala substitution 2. Functionality, performance, expression level are identical 3. No biological or disease significance

question

Developmental expression of heme genes

answer

Please see picture

question

Structure of HbA

answer

Alpha2Beta2. Percentage of normal hemolysate (individuals more than 8 months old) = 92.5%

question

Structure of HbA2

answer

Alpha2Delta2. Percentage of normal hemolysate = 2.5%

question

Structure of HbA1c

answer

Alpha2(Beta-N-glucose)2. Percentage of normal hemolysate = 4.0%

question

What is HbA1c increased in? Decreased in?

answer

Increased in DM. Decreased in hemolytic anemia

question

Structure of HbF

answer

Alpha2Gamma2. Percentage of normal hemolysate = less than 1%

question

What is HbF increased in?

answer

Increased in Beta Thalassemia

question

Structure of HbH

answer

Beta4. Percentage of normal hemolysate = 0%

question

What is HbH increased in?

answer

Increased in Alpha Thalassemia

question

Structure of Hb Bart's

answer

Gamma4. Percentage of normal hemolysate = 0%

question

What is Hb Bart's increased in?

answer

Increased in Alpha Thalassemia

question

Oxygen affinity of HbF (Alpha2Gamma2) vs. HbA (Alpha2Beta2)

answer

question

Thalassemias

answer

Single most common defect - decreased production of a globin chain - "right protein, wrong amount"

question

Hemoglobinopathies

answer

"Wrong protein, right amount"

question

Alpha Thalassemias

answer

question

Fate of surpluse Beta and Gamma chains (Alpha Thalassemias)

answer

question

Beta Thalassemias

answer

question

Fate of surplus Alpha chains (Beta Thalassemias)

answer

question

Hemoglobin S - Beta-globin defect (Hemoglobinopathies)

answer

question

Hemoglobin Electrophoresis

answer

Please see picture

question

Potential therapies for hemoglobin-related diseases

answer

1. Bone marrow transplant (cure) 2. Blood transfusions (and possibly iron chelation therapy) 3. Hydroxyurea treatment to stimulate synthesis of Gamma chains (and HbF) - for Beta globin diseases

question

How might synthesis of Gamma chains help a sickle cell patient?

answer

Formation of HbF helps prevent HbS formation

question

Characteristics of benign tumors

answer

1. Benign tumors are localized and encapsulated (not invasive) 2. Benign tumor cells are more differentiated than cells in malignant tumors; very easy to tell benign tumor cells from normal tissue

question

Characteristics of malignant tumors (cancers)

answer

Invasive and/or metastatic; very difficult to find border of malignant tumors with normal tissue. Locally invasive tumors are also cancers

question

Note on invasive tumors and surgery

answer

question

What is cancer?

answer

question

Metastasis

answer

question

Stages in tumor growth and metastasis

answer

question

Oncogenesis

answer

A multi-step, dynamic and evolutionary process, with each step corresponding to a different genetic mutation(s) in different genes

question

Angiogenesis

answer

Is the formation of new blood vessels in and around tumor. The purpose of angiogenesis is for tumor to obtain more nutrients for faster growth and proliferation

question

Carcinomas (types of cancers)

answer

Cancers of epithelial cells (~90%)

question

Sarcomas (types of cancers)

answer

Cancers of the supporting tissues such as bone, cartilage, fat, connective tissue, and muscle

question

Leukemias (types of cancers)

answer

Cancers of hemopoietic cells (in bone marrow)

question

Lymphomas and myelomas (types of cancers)

answer

Cancers that arise in the immune system

question

Central nervous system cancers (types of cancers)

answer

Cancers that begin in the tissue of the bran and spinal cord

question

Six hallmarks of cancer in 2000

answer

1. Sustaining proliferative signaling 2. Evading growth suppressors 3. Activating invasion and metastasis 4. Enabling replicative immortality 5. Inducing angiogenesis 6. Resisting cell death

question

Sustaining proliferative signaling (hallmarks of cancer in 2000)

answer

Oncogenic signaling

question

Evading growth suppressors (hallmarks of cancer in 2000)

answer

Loss of tumor suppression

question

Activating invasion and metastasis (hallmarks of cancer in 2000)

answer

Invasion and metastasis

question

Enabling replicative immortality (hallmarks of cancer in 2000)

answer

Telomere and telomerase

question

Inducing angiogenesis (hallmarks of cancer in 2000)

answer

New blood vessel formation

question

Resisting cell death (hallmarks of cancer in 2000)

answer

Resistance of apoptosis

question

Four emerging hallmarks of cancer since 2010

answer

1. Avoid immune destruction 2. Tumor-promoting inflammation 3. Genome instability and mutation 4. Deregulating cellular energetics

question

Avoiding immune destruction (hallmarks of cancer since 2010)

answer

Immuno-evasion

question

Tumor-promoting inflammation (hallmarks of cancer since 2010)

answer

Inflammation (enabling characteristics)

question

Genome instability an mutation (hallmarks of cancer since 2010)

answer

Cancer genomics (enabling characteristics)

question

Deregulating cellular energetics (hallmarks of cancer since 2010)

answer

Cancer metabolism

question

Cancer rates are genetically, environmentally, and culturally influenced

answer

question

In addition to genetics, what other factors play significant roles in oncogenesis?

answer

question

Diet's role on certain cancers

answer

question

Cancer lag time

answer

1. There is a good correlation between smoking and lung cancer 2. There is a delay (lag time) of ~20-30 years between smoking and lung cancer

question

How many signaling pathways and processes are found to be mutated and disregulated in pancreatic caner? Mutations in more than how many genes are identified and involve?

answer

13 and 40 respectively. Similar results are also found in brain cancer, breast cancer, and colon cancer

question

Key information from genomic studies of cancer

answer

question

What two types of cancers contain the most genetic mutations?

answer

question

Driver genes

answer

The most important gene mutation(s) at a given stage for oncogenesis to proceed. Drivers may be (usually are) different at different stages of oncogenesis

question

Rider genes

answer

gene mutations that play a very small or no roles in oncogenesis at certain stages

question

Key importance of driver and rider genes

answer

question

Effective anticancer therapies are those that target driver or rider genes?

answer

Driver genes

question

The development an metastasis of human colorectal cancer and its genetic basis

answer

question

Summary of the causes of cancer and oncogenic process

answer

question

Cancer stem cell hypothesis

answer

question

Cancer stem cell model

answer

Tumor cells are heterogeneous and only the cancer stem cell subset (CSC; yellow) has the ability to proliferate extensively and form new tumors. CSC model is well established

question

Clonal evolution model

answer

Tumor cells are heterogeneous, but most cells can proliferate extensively and form new tumors

question

Cancer stem cells (CSC)

answer

question

Proto-oncogenes

answer

NORMAL CELLULAR GENES that encode proteins involved in various aspects of cell growth and cell proliferation

question

Oncogene

answer

Cancer-producing genes that are DERIVED FROM PROTO-ONCOGENES BY VARIOUS TYPES OF GENETIC MUTATIONS

question

Proto-oncogenes and oncogenes are . . .

answer

Growth (cell proliferation) promoting genes

question

Tumor suppressor genes are . . .

answer

Growth-suppressing (-decelerating or-inhibiting) genes

question

What are the seven types of proteins that participate in controlling cell growth (any may be involved in oncogenesis)

answer

question

Growth factors in cancer

answer

Normal growth factors (proteins) become oncogenic when they are OVER-EXPRESSED (over-produced)

question

Name two important proto-oncogene receptor proteins

answer

1. HER2 2. EGF Both are a receptor tyrosine kinase (RTK)

question

HER2

answer

The dimerized protein is constitutively active as a kinase - human breast cancer

question

What is an effective treatment for one type of breast cancer involving HER2 receptor?

answer

Herceptin is a very effective drug treating one type of breast cancer in which Her2 receptor gene is mutated into Neu gene

question

EGF receptor

answer

Dimerization of two receptor proteins in the absence of normal EGF-related ligand

question

What types of cancers is EGFR involved in?

answer

EGFR is involved in many types of lung cancers, drugs targeting different EGFR mutations are effective in treating lung cancers

question

Important of tyrosine kinases

answer

question

Ras

answer

Is a GTP-binding protein. Constitutively active Ras protein leads to uncontrolled cell growth and cancer

question

Importance of Ras mutations (growth signal transducer)

answer

question

What are two important proto-oncogene products following serum stimulation of quiescent 3T3 cells?

answer

1. c-Fos 2. c-Myc One of the earliest effects of growth factors is to induce transcription of c-Fos and c-Myc proto-oncogenes

question

Fos and Myc

answer

question

The types of genetic mutations in the gene mutations include (3)?

answer

1. Point or deletion mutations 2. Gene amplification 3. Chromosome rearrangement

question

A proto-oncogene can become an oncogene by?

answer

1. Mutations in the regulatory sequence; promoter 2. Mutations in the coding sequence in the gene 3. Chromosomal translocation 4. Gene amplification

question

Philadelphia Chromosome

answer

question

What type of cancer is a result of the Philadelphia chromosome?

answer

CML

question

Tumor suppressor genes

answer

question

RB gene

answer

question

Two-hit hypothesis

answer

question

The two-hit origin of cancer theory applies only to what genes?

answer

Tumor suppressor genes, not oncogenes. It applies to the same tumor suppressor gene, not two different tumor suppressor genes

question

p53 gene

answer

1. Tumor suppressor, transcription factor 2. Mutated or deleted in > 50% of all human cancers 3. May be the most important gene in human cancer 4. Cause of the genetic diseases Li-Fraumeni Syndrome

question

The p53 gene is involved in (3)

answer

1. DNA damage repair 2. Cell cycle checkpoint control 3. Apoptosis

question

Normal function of oncogenes (proto-oncogene)

answer

Cell growth-promoting (proto-oncogene)

question

Normal function of tumor suppressor genes

answer

Cell growth-suppressing

question

Consequences of mutation/genetic trait of oncogenes (from proto-oncogenes)

answer

GAIN of function. Genetic trait: Dominant (one allele), somatic mutations

question

Consequences of mutation/genetic trait of tumor suppressor genes

answer

LOSS of function. Genetic trait: Recessive (both alleles) *but classified as dominant*, genetic inheritance

question

G1 phase

answer

Rapid growth and centriole replication. 8-10 hours

question

S phase

answer

Chromosome replication (DNA synthesis). 6-8 hours

question

G2 phase

answer

Growth and final preparations for cell division. 4 to 6 hours

question

Mitosis and Cytokinesis

answer

PMAT; Prophase, Metaphase, Anaphase, and Telophase followed by Cytokinesis

question

G1/S checkpoint of the mitotic cell cycle is controlled by what two genes?

answer

1. p53 2. RB

question

What proteins are used during the G2 phase of the mitotic cell cycle?

answer

Cyclins + CDKs; A group of proteins whose function is to regulate the progression of a cell through the cell cycle and whose concentrations rise and fall throughout the cell cycle

question

Telomere

answer

Is a region of repetitive DNA at the end of a chromosome, which protects the end of the chromosome from destruction (similar to the plastic caps at the ends of shoelace)

question

What replenishes telomeres after they are shortened during cell division?

answer

Telomerase

question

Senescence

answer

Aging of the cell. As telomeres grow shorter, eventually cells reach the limit of their replicative capacity and progress into senescence

question

What happens to the telomere in cancer cells?

answer

question

Compared to normal cells, cancer cells' telomerase activity is ________ and telomeres are _________ - two of the key reasons that cancer cells are immortalized

answer

Higher, longer respectively

question

RNA and DNA viruses as cancer-producing agents

answer

1. Both RNA and DNA viruses can carry oncogenes 2. Both RNA and DNA viruses can induce cancer in animals and humans

question

Oncogenes that function in viral replication cycle are characteristic of what type of virus?

answer

question

Epstein-Barr virus can lead to what type of cancer?

answer

Burkitt's Lymphoma

question

HPV can lead to what type of cancer?

answer

Cervical cancer

question

Hepatitis B virus can lead to what type of cancer?

answer

Liver cancer

question

Human T-cell lymphotrophic virus can lead to what type of cancer?

answer

Adult T-cell leukemia

question

Kaposi's sarcoma-associated herpes virus can lead to what type of cancer?

answer

Kaposi's sarcoma

question

Genomic structures of retroviruses

answer

1. There are two mechanisms for retroviruses to cause cancer - FAST OR SLOW tumor-forming 2. The genome of fast tumor-forming retrovirus contains an oncogene (onc)

question

Fast tumor-forming retrovirus

answer

Contains an oncogene; onc

question

Slow tumor-forming retrovirus

answer

Activation of the c-myc proto-oncogene by retroviral promoter and enhancer insertions

question

HPV can cause cervical cancer, how?

answer

Once inside the cells of their host, HPV synthesizes a protein designated E7 - an oncogene product. E7 binds and inactivates p53 which causes E2F to start promoter "on" and cell begins mitosis

question

Carry oncogenes

answer

Both DNA and RNA viruses

question

Carry tumor suppressor genes

answer

Neither DNA or RNA viruses

question

Carry oncogene as part of a normal viral genome

answer

Only DNA viruses

question

Carry oncogene that has normal function in viral cycle

answer

Only DNA viruses

question

How many mutations are needed for developing cancer?

answer

question

Kinetics of tumor appearance in female transgenic mice carrying transgenes driven by the mouse mammary tumor virus (MMTV) breast-specific promoter

answer

question

If therapies can be targeted against cancer stem cells, then the might be more effectively kill the cancer stem cells

answer

question

Most tumor suppressors are involved in . . .

answer

1. Cell cycle regulation 2. DNA repair 3. Apoptosis Several times more tumor suppressor genes are found mutated than proto-oncogenes

question

BRCA1 and BRCA2 are tumor suppressor genes involved in what type of familial cancer?

answer

Breast cancer

question

Most familial cancers are consequences of what type of gene mutations?

answer

Tumor suppressor genes

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