question

What is cancer?

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- not a single disease, but rather a heterogeneous group of disorders brought about by the presence of cells that do no undergo normal cell division - cancer cells divide rapidly and continuously, creating tumors that crowd out normal cells - some cells of tumors are able to separate and travel to distant sites and develop another tumor

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Cancer cell

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- in a cancer cell, one or more of the stimulatory and/or inhibitory signals of cell division regulation are disrupted, causing cells to proliferate at high rates - gradually lose their regular shape and boundaries --> form a distinct mass of abnormal cells known as a TUMOR

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Benign tumor

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- tumor characterized by localized cancerous cells --> they do not proliferate to other parts of the body

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Malignant tumor

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- characterized by cancerous cells that invade other tissues in the body

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Metastasis

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- the process that cancerous cells undergo when they travel to other sites in the body and establish secondary tumors

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Describe how early observations of cancer suggested it could result from genetic damage

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- many agents causing mutations also caused cancer - some cancers are consistently associated with particular chromosome abnormalities - some specific types of cancers tend to run in families

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What are the major problems that arise from observations that cancer is a result of genetic damage?

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- if cancer is truly inherited, then every cell in the body should have cancer-causing genes, making all cells eventually cancerous - In cancers that "run in families", tumors usually appear only in certain tissues and often show up at certain older age - also, many cancers don't "run in families", and sometimes rare cases occur in these families with no history of the disease

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Knudson's multistep model of cancer

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- suggests that cancer is the result of a multistep process that requires several mutations - if one or more of the mutations is inherited, fewer additional mutations are required for cancer to start --> as a result, cancer will tend to run in families

question

Current understanding of cancer

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- understand it to be a fundamentally genetic disease - given that few cancers are inherited, many tumors arise from somatic cell mutations + these mutations can accumulate throughout a person's lifespan through spontaneous mutations or in response to environmental mutagens

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Describe how cancer begins and progresses

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- begins when a single cell undergoes a mutation that causes the cell to divide abnormally and at rapid rates - as the cell continues to divide, it gives rise to an increasing number of clone cells, which all carry the same mutation - these proliferating cells soon outgrow normal, healthy cells - an additional mutation can arise in some of the cancerous clone cells, further enhancing the ability of the cells to proliferate --> cells carrying additional mutations soon become the most abundant + soon cells with more mutations take over as they proliferate faster

question

Clonal evolution of tumors

answer

- a process in which tumor cells acquire more mutations that allow them to become increasingly more aggressive in their proliferation

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What can increase the rate of cancer?

answer

- any genetic defect that allows more mutations to arise will accelerate progression + genes that regulate DNA repair are often found mutated in cells of advanced cancers --> these cells, without the normal regulation from DNA repair genes, are more likely to retain mutations - mutations in genes that affect chromosome segregation can contribute to evolution of cancer

question

Signals that regulate cell division can be divided into two basic types. What are they?

answer

1. molecules that STIMULATE cell division 2. molecules that INHIBIT cell division - cell division is affected by both of these kinds of molecules at the same time to give the proper speed of cell division

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Oncogenes

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- mutated dominant-acting stimulatory genes that cause cancer - in this case, it is a stimulatory gene that is made hyperactive, or simply active at inappropriate times - mutations are usually dominant - make up about 90% of cancer genes

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Tumor-suppressor genes

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- inhibitory genes that cause cancer - cancer is stimulated when inhibitory genes are made INACTIVE - mutated inhibitory genes usually have recessive effects because both copies must be mutated in order to remove all inhibition - make up about 10% of cancer genes

question

proto-oncogenes

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- normal cellular genes that carry DNA sequences that are closely related to viral oncogenes - responsible for basic cellular functions in normal cells, but when mutated, these genes become oncogenes - proto-oncogenes are more likely to undergo mutation or recombination within a virus, which is why viral infection is often associated with cancer

question

Describe the various ways in which proto-oncogens can be converted into oncogenes by a virus

answer

- the sequence of the proto-oncogen may be altered or truncated as it is being incorporated into the viral genome + mutated copy of the gene may produce an altered protein that can cause uncontrolled cell proliferation - through recombination, a proto-oncogen may end up next to a viral promoter or enhancer --> causing the gene to be overexpressed - proto-oncogen in a host cell may be altered when a virus inserts its own DNA into the gene --> disrupts normal cell function

question

Describe a simple way that oncogenes can be identified

answer

- selected fragments of DNA are added into cells of a culture - some of the cells take up the DNA: + if the cells become cancerous, then the DNA fragment added must have contained an oncogene - the fragments are then sequenced and the oncogene can be identified

question

Why are tumor-suppressor genes harder to identify?

answer

- given that these genes inhibit cancer, and that the failure of their function causes cell proliferation, they cannot be found by adding them to cells and looking for cancer - in addition, they are recessive, so both alleles must be mutated before inhibition is removed

question

Loss of heterozygosity

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- the inactivation of the remaining wild-type allele in heterozygotes - heterozygotes refer to tumor-suppressor genes that have one mutant allele, which are now predisposed to cancer

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Describe a common mechanism for "loss of heterozygosity"

answer

- a deletion on the chromosome that carried the normal copy of the tumor-suppressor gene

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haploinsufficiency

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- the appearance of the trait in an individual cell or organism that is heterozygous for a normally recessive trait - in other words, sometimes the mutation of a single allele of a tumor-suppressor gene is sufficient to cause cancer (even though these genes are recessive)

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How is haploinsufficiency possible?

answer

- appears to be due to dosage effects - the heterozygote produces only half as much of the product encoded by the tumor-suppressor gene - Usually this amount is sufficient for the gene to continue its inhibitory functions, but it is still less than optimal amount --> when other factors combine, it could allow for haploinsufficiency

question

cyclin-dependent kinases (CDKs)

answer

- enzymes that add phosphate groups to other proteins, which is one of the key events of cell cycle control - phosphorylation can either activate or inactivate the protein - CDKs are functional ONLY when they associate with another protein, called CYCLIN

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Cyclin

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- the protein that binds to and activates cyclin-dependent kinases - when bound to CDK, cyclin will specify which proteins the CDK will phosphorylate

question

Describe the G1 to S transition

answer

- when the cell transitions from the G1 stage to the S stage (DNA replication), it must pass through the G1/S checkpoint - the retinoblastoma (RB) protein prevents cells from passing through the G1/S checkpoint + this protein binds to E2F and keeps it inactive - cyclin D and E increase in concentration and combine with their CDKs + these CDKs phosphorylate molecules of RB --> once the process is complete, RB becomes inactive - without the inhibitory effects of RB, the E2F protein is released, and it stimulates the transcription of genes that produce enzymes necessary for DNA replication --> cell moves to S stage of the cell cycle

question

Describe the G2 to M transition

answer

- cyclin B combines with a CDK to form an inactive complex: MITOSIS-PROMOTING FACTOR (MPF) + Once MPF is formed, it can only be activated by the removal of a phosphate group - in the beginning of G1, cyclin B levels are low --> MPF levels are low - as the cell cycle continues, more cyclin B is produced, increasing the levels of MPF + near end of G2, MPF levels reach a critical point, which commits the cell to divide - G2/M checkpoint is at the end of G2 phase before cell enters mitosis

question

Active form of Mitosis-promoting factor (MPF)

answer

- the active form, which occurs with the removal of a phosphate group, phosphorylates other proteins - these proteins bring about many of the events associated with mitosis - at the end of metaphase, cyclin B is abruptly degraded, thus lowering the amounts of MPF - high levels of active MPF stimulate mitosis - low levels of MP bring a return to interphase conditions

question

Spindle-assembly checkpoint

answer

- checkpoint in metaphase - delays the onset of anaphase until all chromosomes are lined up on the metaphase plate and sister kinetochores are attached to spindle fibers from opposite poles - if all chromosomes are not aligned, the checkpoint blocks the destruction of cyclin B + this constant production of cyclin B keeps MPF active and keeps the cell in a mitotic state

question

Give some examples of mutations in the cell-cycle that could lead to cancer

answer

- mutations in the gene that encodes RB protein (which holds the cell in G1 until DNA is ready for replication) has been associated with many cancers + the mutation allows cells to pass through the G1/S checkpoint without the normal controls - a mutation in the gene that encodes cyclin D (stimulates the passage of cells through G1/S checkpoint) causes it to be overexpressed - p53, a tumor-suppressor gene, regulates an inhibitor of CDK activity when mutated

question

Cancer cells and apoptosis

answer

- cells normally have the ability to assess themselves and undergo apoptosis if they are damaged - cancer cells usually have chromosome mutations, DNA damage, and other cellular abnormalities that would NORMALLY stimulate apoptosis and prevent their proliferation

question

p53

answer

- the ability of a cell to initiate apoptosis in response to DNA damage is dependent on this tumor-suppressor gene - also a tumor-suppressor gene that prevents cell division when the DNA is damaged - encoded by the TP53 gene - inactive in many human cancers

question

Describe the 3 parts of a receptor that would be utilized in a signal-transduction pathway

answer

1. an extracellular domain that protrudes from the cell and binds to a signaling molecule 2. transmembrane domain that passes across the membrane and sends signal to the cell 3. an intracellular domain that extends into the cytoplasm --> undergoes a chemical conformational change once signaling molecule binds

question

What is the Ras signal-transduction pathway?

answer

- a pathway that plays an important role in the control of the cell cycle

question

What is the order of events in the cascade of a Ras signal-transduction pathway?

answer

1. Growth factor (i.e. epidermal GF = EGF) binds to growth factor receptor (EGFR) 2. Conformational change in receptor occurs and the addition of phosphate groups 3. Addition of phosphate groups allow adaptor molecules to bind to receptor 4. Adaptor molecules link an inactive molecule of Ras protein --> these molecules then stimulate the activation of Ras 5. Activated Ras activates the protein Raf --> after activation, Ras goes back to inactive form 6. Activated Raf sets off a cascade of reactions, ending in the activation of protein MAP kinase 7. Activated MAP kinase moves to nucleus and activates various transcription factors, which stimulate transcription of genes in cell cycle

question

When is the Ras protein inactive? active?

answer

- In the inactive form, the protein is bound to GDP - in the active form, the protein releases GDP to form GTP

question

What would happen if mutations occurred in the genes that produce the RAS protein?

answer

- there is a mutation that would produce Ras proteins that could bind to GTP but would not be able to hydrolyze it to GDP - as a result, Ras would be stuck in its active form, continuously stimulating cell division + this could contribute to cancer

question

Describe 3 factors that affect the rate at which mutations arise in a cell

answer

1. the rate at which errors arise in the course of replication and afterwards 2. the efficiency with which those errors are corrected 3. whether errors are corrected by DNA-repair systems + defects in genes that encode components of these repair systems are often associated with cancers

question

What can defects in DNA-repair systems contribute to?

answer

- the mutation rates of individual cells - the generation of chromosome rearrangements and genomic instability + given that DNA-repair systems often make single and double-stranded breads, if the breaks are not repaired, there will be rearrangements

question

Telomerase and progression of cancer

answer

- inappropriate activation of telomerase can lead to cancer - ends of telomeres cannot be replicated and so chromosome get smaller after each division, which eventually leads to chromosome destruction in SOMATIC cells + germ cells have a way around this problem using telomerase enzyme that replicates chromosome ends - in many tumor cells, the telomerase enzyme is expressed, which gives the cell the ability for unlimited cell division

question

Genes that promote vascularization and the spread of tumors

answer

- growth of new blood vessels (angiogenesis) supplies oxygen and nutrients to tumors - angiogenesis is usually carefully regulated by other proteins in normal cells - in tumor cells, genes encoding these proteins is often overexpressed, and inhibitors of angiogenesis-promoting factors may be inactivated or underexpressed

question

MicroRNAs (miRNAs)

answer

- class of small RNA molecules that pair with complementary sequences on mRNA and degrade the mRNA or inhibit its translation

question

miRNAs and cancer

answer

- many tumor cells exhibit reduction in the expression of miRNAs - research indicates that miRNAs play a role in later stages of tumor progression - lowered levels of miRNAs may lead to cancer by allowing oncogenes that are normally controlled by miRNAs to be expressed at high levels - also some miRNAs are known to suppress tumor development, so when mutated, they will increase likelihood of cell proliferation

question

International Cancer Genome Consortium

answer

- coordinates efforts to determine the genomic sequences of tumors - a major challenge is to determine the difference between driver and passengers mutations

question

Driver mutations

answer

- mutations that drive the cancer process - they directly contribute to the development of cancer - include mutations in oncogenes, tumor-suppressor genes, DNA-repair genes

question

Passenger mutations

answer

- mutations that arise randomly in the process of tumor development - do not contribute to the cancer process - include mutations in introns and other DNA that is not transcribed/translated - they also arise within protein-encoding genes

question

Chromosome mutations and cancer

answer

- it has been determined that chromosome mutations appear to both cause cancer and result from it

question

Name the types of chromosome rearrangements that are associated with cancer

answer

- deletions: result from loss of one or more tumor-suppressor genes - inversions - translocations

question

Describe how inversions and translocations can help lead to some cancers

answer

- chromosomal breakpoints associated with these rearrangements could lie within tumor-suppressor genes --> disrupting their function - these rearrangements may bring together sequences from 2 different genes - may produce cancer by the transfer of potential cancer-causing gene to a new location, where it can be activated by various regulatory sequences

question

How are chromosome abnormalities brought about?

answer

- some cancer researchers believe that cancer is initiated when genetic changes take place, which causes the genome to become unstable - this instability generates numerous chromosome abnormalities which then alter the expression of oncogenes and tumor-suppressor genes

question

Human papilloma viruses

answer

- about 95% of women with cervical caner are infected with HPV - this is a DNA virus + unlike retroviruses, do not undergo reverse transcription, but do integrate into the host chromosome

question

Describe how retroviruses can cause cancer in their host cells

answer

- may mutate and rearrange host genes, which can convert proto-oncogenes into oncogenes - can alter the expression of host genes - retroviruses often contain strong promoters that if inserted near a proto-oncogene, these promoters may stimulate high levels of expression of the proto-oncogene, leading to proliferation

question

How does HPV cause cervical cancer?

answer

- by producing a protein that attaches to and inactivates RB and p53 - both of these proteins play key roles in the regulation of the cell cycle - when the proteins are inactivated, cells are stimulated to progress through the cell cycle and divide without the normal controls

UNIT 7: Chpt 23 – Flashcards

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