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Cell cycle

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series of events that cells go through as they grow and divide; consists of phase: M, G1, G0, S, G2

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M-phase time

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1 hour

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Interphase time

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10-12 hours; no upper limit

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S-phase time

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6-8 hours

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G2 phase time

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2-4 hours

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G1 phase time

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very variable

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Interphase subdivisions

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G1 (gap 1), S (DNA synthesis phase) and G2 (gap 2)

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G0

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in the absence of growth factors, the cell leaves the cell cycle at G1 and enters the resting phase (this phase)

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Restriction point

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point when cells become committed to enter the cell cycle

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M phase

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mitosis and cytokinesis

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Mitosis

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separation of daughter chromatids; division of nucleus (karyokinesis); microtubule-dependent

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Cytokinesis

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part of M-phase; division of the cytoplasm; actin dependent

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Stages of mitosis

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prophase, prometaphase, metaphase, anaphase, telophase (PPMAP)

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Prophase (mitosis)

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stage 1; chromosomes condense; nucleolus disappears; cytoplasmic microtubules break down; spindles being to form; centrioles migrate to poles

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Prometaphase (mitosis)

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stage 2; chromosomes shorten & thicken, spindle forms between centrioles, moved to poles of the cell, kinetichores begin attaching to microtubules

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Metaphase (mitosis)

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stage 3; pulling in between the kinetochore tubules results in the chromosomes and lining up at the metaphase plate

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Anaphase (mitosis)

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stage 4; sister chromatids have separated and are now chromosomes; they are being pulled to opposite ends of the cell; kinetochore microtubules shorten; polar microtubules lengthen and slide; cleavage furrow appears and actin band form a contractile ring (start of cytokinesis)

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Telophase (mitosis)

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stage 5; nuclear envelope forms; spindles disappear; nuclear envelope forms; nucleolus re-forming; chromosome decondense; midbody contains spindle remnants

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Return to interphase

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cytokinesis complete; cytoplasmic microtubules reforming

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Spindle formation

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depends on the centrosome; a microtubule organising centre

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Spindle formations contains

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a pair of centrioles

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Centrosome location during interphase

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adjacent to the nucleus

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Centrosome

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a structure present in the cytoplasm of animal cells that functions as a microtubule-organising centre and is important during cell division; composed of two centrioles

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Centrioles

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cylindrical structures about 0.5 x 0.2 micrometers in diameter; made up of 9 triplets of microtubules; can act as a template for making cilia

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Centriole duplication at each pole begins during

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interphase

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Procentriole

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daughter centriole; grows out at right angles to the base of the mother centriole; one at each pole

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By late _____ phase, the procentriole is full length but still attached

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G2

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Mother/daughter centriole pairs seprate and spindles forms between them during the onset of ______

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mitosis

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Detachment of mother and daughter centrioles occurs in _____ phase

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G1

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Mitosis promoting factor

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causes entry into mitosis; cell fusion experiments revealed its existence

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Rao and Johnston, 1970

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revealed the existence of mitosis promoting factor; shows that mitotic cells contain an inducer of mitosis (=MTF) which is dominant over all other phases of the cell cycle; what the MTF actually is not discovered

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Fusion of a mitotic cell with an interphase cell

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causes the interphase nucleus to enter mitosis prematurely

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Mitotic cell + G1 cell fusion

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results in single, thin chromosomes that have not replicated yet

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Mitotic cell + S cell fusion

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replication forks everywhere; some replicated bits and some un-replicated bits of the genome; chromatin gets smashed to pieces > complete chaos

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Mitotic cell + G2 fusion

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chromosomes become visible but much less visible than mitotic cell; thicker chromosomes than G1 chromosome; duplicated structures

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Frog eggs

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MPF from them purified from them; found the MPF in it; found that the MPF is a cyclic-dependent protein kinase (already discovered in something else)

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Protein kinase

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an enzyme that transfers phosphate groups from ATP to a protein, thus phosphorylating the protein

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Protein kinase

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made of a catalytic subunit and a regulatory subunit

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Cdk1

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catalytic subunit; first identified by Paul nurse through cell cycle genetics in yeast

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Cyclin B

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regulatory subunit; first identified by Tim Hunt; in cleaving sea embryos; drives the mitosis;

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Levels of Cdk1 during mitosis

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changes little during the cell cycle

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Levels of Cyclin B during mitosis

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accumulates steadily during interphase and peaks during M

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Degradation of Cyclin B

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essential to exit mitosis

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S phase entry

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also depends on a dominant inducer

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Fusion of S phase cell with G1 cell

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causes G1 nucleus to entre S phase prematurely

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SPF

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cyclin-dependent kinase consisting a regulatory and catalytic subunit; triggers firing of replications origins and the initiation of DNA synthesis

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Cdk2

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catalytic subunit of SPF; remains steady throughout cell cycle

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Cyclin E or Cyclin A

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regulatory subunits of SPF

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Cyclin E

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accumulates and peaks at the start of S phase but drops midway through

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Cyclin A

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accumulates at the start of S phase and drops off at the end of G2 phase

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Quiescence

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inactivity, stillness

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G0 cells

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lack the machinery for replicating DNA because transcription of genes needed for the cell cycle entry by E2F transcription factors is repressed by Rb

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E2F

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transcription factors that allow replicating DNA to transcribe the genes needed for cell cycle entry;

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E2F target genes include

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thymidine kinase, DNA polymerase alpha, Cdc6, Cdk1, cyclin A, cyclin E, E2F-1

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Rb gene

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protein that repress E2F transcription factors necessary for a cell to enter the cell cycle

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Mutations in Rb gene

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responsible for retinoblastoma and are found at high frequency in many other tumours i.e. Rb acts as a tumour suppressor; inherited results in high susceptibility

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Retinoblastoma

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tumour arising from a developing retinal cell; found in children

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Passage of the restriction point (R)

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repression of EF2 is removed by phosphorylating Rb which is believed to correspond with...

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Activate protein kinase complex

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ckd4 or ckd6 plus cyclin D1; phosphorylate Rb

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Cyclin D1 expression

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point of convergence of numerous signalling pathways; expression strongly growth factor dependent

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Over-expression of cyclin D1

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due to gene amplification or chromosome translocation; can drive entry into the cell cycle in the absence of growth factor stimulation

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Oncogene

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cancer-causing genes that are formed due to mutations; e.g. mutated cyclin D1

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Over-expression of cyclin D1 due to gene application

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common in breast cancers

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Over-expression of cyclin D1 due to chromosome translocation

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common in B-cell lymphomas

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Cell cycle deregulation

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found in many cancers

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Most cancer cells have a

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reduced dependence on growth factors to enter the cell cycle

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Common cell cycle deregulations (3)

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1) loss of Rb 2) upregulation of cyclin D 3) constitutive activation (continuous syntheis regardless of inducer of repressor molecules)) of growth factor signalling pathway

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Pathway typically mutated in cancer cells

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Ras-Raf-MAPK pathway

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Ras-Raf-MAPK pathway location

answer

downstream of receptor tyrosine kinase

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Growth factor action

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(1) binds to GF receptor on plasma membrane, which have a tyrosine kinase unit which is activated (2) TK enzyme unit recruits Ras-GTP (3) Ras recruits another protein kinase, Raf (4) activates MAP kinase cascade (5) alters transcription in the nucleus

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GF affects of transcription in nucleus

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increases the activity of transcription factors (fos, jun, myc) resulting in increased production of Cyclin D

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MAP Kinase pathway

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only active when phosphorylated by MAPK; acts as an amplification pathway; amplification of transcription

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MAPK

answer

only active when phosphorylated by MAPKK

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MAPKK

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only active when phosphorylated by MAPKKK

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Raf-1

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MAPKKK

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Ras

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activated by growth factors by causing the replacement of its bound GDP with GTP

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Active form of Ras

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Ras-GTP

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G protein

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a GTP-binding protein that relays signals from a plasma membrane signal receptor; known as a G protein-coupled receptor, to other signal transduction proteins inside the cell

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GEF

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guanine nucleotide exchange factors (GEFs) activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP)

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Oncogenic Ras

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has point mutations in codons 12, 13 or 61; inhibits GTPase activity locking the Ras into active configuration (Ras-GTP)

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Ras mutations found in ____% of human cancer cells

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30

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Ras mutations found in ____% of pancreatic cancer cells

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90

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Other ways of deregulating the Ras-Raf-MAPK pathway in cancer

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(1) autocrine production of growth factors (2) constitutive activation of growth factor receptor mutation (3) over-expression of growth factor receptor though gene amplification

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Autocrine

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term for hormones that act on same cells that secrete them

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Constitutive activation

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an appreciable level of activation existing even when no receptor ligand is present;

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Constitutive activation of GF receptor mutation is found in what cancer

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found in EGFR in some lung cancers

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Over-expression of GF receptor through gene amplification is found in what cancer

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found in HER2 (EGFR family) in a subset of breast cancers

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Herceptin

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monoclonal antibody to HER2; used to target some breast cancers

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EGFR

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epidermal growth factor receptor

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First cell cycle checkpoint

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prevent cells from entering S phase with damaged DNA

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Second cell cycle checkpoint

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prevent cells with incomplete or damaged DNA from entering mitosis

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Third cell cycle checkpoint

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prevent cells in metaphase from entering anaphase before all the chromosomes are attached to the mitotic spindle

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Tumour suppressor p53

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involved in first and second cell cycle checkpoint

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Activation of tumour suppressor p53

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(1) p53 is phosphorylated following DNA damage (2) activate p53 induces transcription of p21

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p21

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inhibits activation of cyclin dependent kinase (Cdk) by cyclin and prevents entry into S-phase or M-phase

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Some transcriptional targets of p53

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trigger apoptosis

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Mutated p53

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Will increase the likelihood of cancer because damaged DNA can go through the cell cycle

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Unattached kinetochores

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generates a signal that prevents entry into anaphase

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Mad2 (for e.g.)

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product of genes essential for proper chromosome segregation

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Role of Mad2 precursor genes

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prevent anaphase onset; are displaced when spindle attachment occurs

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Spindle assembly checkpoint

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defective in some cancers, leading to chromosome instability; causes non-disjunction

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Deregulation of the cell cycle in cancer depends on

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(1) gain of function mutations in genes regulating growth factor signalling pathways to generate oncogenes (2) loss of function mutations in genes whose products repress the cell cycle

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Mutations in certain genes, e.g. _____, results in a gain of function in GF signalling pathways > oncogenes

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Ras

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Mutations in certain genes, e.g. _____ and _____, results in a loss of function > failure to repress the cell cycle

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Rb and p53

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Incidence of cancer increased rapidly with _____

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age

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Rate of increases suggests _______, ______ genes must be mutated, typically

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multiple, independent

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Minimum number of gene mutations required to cause cancer

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5-7

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Properties that must be acquired by a mutated cell to cause cancer (6 items)

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(1) loss of growth factor dependence (2) immortality (3) resistance to apoptosis (4) angiogenesis (5) tissue-invasion (6) metastasis

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Angiogenesis

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the process through which the tumor supports its growth by creating its own blood supply

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Systolic pressure

answer

occurs when the ventricles contract; the highest pressure against the walls of an artery

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Diastolic pressure

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occurs when the ventricles are relaxed; the lowest pressure against the walls of an artery

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Mean pressure is the highest in which blood vessel

answer

aorta

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Mean pressure (mmHg) is the lowest in which blood vessel

answer

vena cava

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Lumen diameter of the aorta

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25 mm

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Lumen diameter of the arteries

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4 mm

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Lumen diameter of arterioles

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20 micro meters

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Lumen diameter of capillaries

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5 micro meters

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Lumen diameter of venules

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20 micro meters

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Lumen diameter of veins

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5 mm

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Lumen diameter of vena cava

answer

30 mm

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Wall thickness of aorta

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2 mm

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Wall thickness of arteries

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15 micro meters

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Wall thickness of capillaries

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1 micro meter

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Wall thickness of venules

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2 micro meter

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Wall thickness of veins

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0.5 mm

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Wall thickness of vena cava

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1.5 mm

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Blood pressure across blood vessels (highest to lowest)

answer

aorta (systolic level) > arteries > arterioles (diastolic level) > capillaries > venules > veins > vena cava

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Arterial system

answer

carries blood away from the heart

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Venous system

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carries blood towards the heart

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Lymphatic system

answer

composed of a network of vessels, ducts, nodes, and organs; provides defence against infection.

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