Cancer and Cell Cycle Regulation Cancer, Cell communication and the Cell Cycle I. Cell Cycle – Chapter 18 You will not be responsible for: details of S-CdK function mechanisms of spindle assembly and anaphase specific details of the caspase cascade & bcl-2 family topics on extracellular signals (pp 636- 640) not covered in class Review mitosis on your own  Panel 18-1, etc Read on your own about cytokinesis in plant and animal cells pp 630 - 633 Questions in this chapter you should be able to answer: Chapter 18: 1 - 5, 10, 12, 13, 14, 16, 17, 20, 25, 26 all but C, 28, 30 Cancer and Cell Cycle Regulation

Table 18–1 Some Eucaryotic Cell-Cycle Times What are the stages of the cell-cycle? -- a review G1 S G2 M G0 Table 18–1 Some Eucaryotic Cell-Cycle Times Cell type Cell cycle time Early frog embryo cells ~30 minutes Yeast cells 1.5–3 hours Intestinal epithelial cells ~12 hours cultured fibroblasts ~20 hours Human liver cells ~1 year Cancer and Cell Cycle Regulation

Cancer and Cell Cycle Regulation Tumor suppressor proteins are ‘Gatekeepers’ and ‘Caretakers’ of the cell Stop Go Die Cancer and Cell Cycle Regulation

Cancer and Cell Cycle Regulation Mutated Tumor Suppressor Genes disable the corresponding Tumor Suppressor Proteins . . . Cells divide when they shouldn’t Cells do not die when they should Cells progress toward metastasis Cancer and Cell Cycle Regulation

Should trigger apoptosis Cells of cancers accumulate numerous chromosomal abnormalities Deletions Translocations Inversions Duplications Meningioma karyotype Aneuploidy - #s 7, 9, 20 Missing homolog - #1, 17, Y Translocations - #s 2, 6, 7 Should trigger apoptosis Tick and Sick-6

Some examples of inactivated Tumor Suppressor Proteins and Oncogenes Tick and Sick-6

Cancer and Cell Cycle Regulation Tumor Suppressor Proteins are part of the “Cell-cycle Control System” The ‘Checkpoint’ model How are they controlled? -- intracellular and extracellular signals What are the effectors -- lots of kinases & phosphatases Cancer and Cell Cycle Regulation

Cancer and Cell Cycle Regulation How is cell cycle progress studied? Different systems -- yeast: cell cycle mutations -- frog: big dividing embryos -- sea urchin & clam: many embryos Asynchronously dividing cells DNA/nucleus staining Flow cytometry Synchronously dividing cells DAPI stained cells Ques 18-2 Where are G1,S,G2, & M stage cells? Cancer and Cell Cycle Regulation

Cancer and Cell Cycle Regulation What did study of frog embryos reveal about the control system? Be sure to read How we know Frog egg cytoplasmic transfer experiments Something in the cytosol triggers mitosis -- called MPF Activity of MPF oscillates during the cell cycle What is MPF? Cancer and Cell Cycle Regulation

Cancer and Cell Cycle Regulation What did sea urchin & clam embryos reveal? Population of synchronously dividing embryos S35 labeling, SDS-PAGE, autoradiography Revealed cyclic synthesis & breakdown of certain proteins Called cyclin Cancer and Cell Cycle Regulation

Table 18–2 The Major Cyclins and Cdks What do we know about MPF & cyclin? MPF is a cyclin bound to a Cdk ‘cyclin-dependent protein kinase’ = M-Cdk Several Cyclins and Cdks -- regulate different cell cycle events Table 18–2 The Major Cyclins and Cdks of Vertebrates Cyclin–Cdk Complex Cyclin Cdk partner G1-Cdk cyclin D Cdk4, Cdk6 G1/S-Cdk cyclin E Cdk2 S-Cdk cyclin A Cdk2 M-Cdk cyclin B Cdk1 Cancer and Cell Cycle Regulation

Cancer and Cell Cycle Regulation How is cyclin-CDK activity regulated? Two processes 1. Synthesis & destruction of cyclin -- ubiquination -- proteasomes 2. Inactivation & activation -- Activating/inhibitory Kinases/phosphatase -- Pos feedback  rapid activation Cancer and Cell Cycle Regulation

Cancer and Cell Cycle Regulation How do cyclin-cdk’s trigger cellular events? S-Cdk triggers DNA replication -- activates replication origins -- blocks reactivation What does activated M-CDK do? Phosphorylates H1 histone (triggering C’some condensation) Disassembly of nuclear lamina Changes behavior of microtubules -- phosphorylates MAPs etc…?? Cancer and Cell Cycle Regulation

Cancer and Cell Cycle Regulation How does activated S-Cdk trigger DNA replication? Origin of Replication Complex (ORC) CDC-6 rises during G1 -- helps build replication fork complex -- helicase, polymerase, etc S-CDK activates replication complex -- inhibits ORC Cancer and Cell Cycle Regulation

Cancer and Cell Cycle Regulation Figures 18-14 + 18-15 How do checkpoint proteins (i.e.,TSPs) suppress cell division? P53, BRCA1, P21 and Rb are all TSPs -- loss of both alleles necessary Why? P53 can also trigger apoptosis Cancer and Cell Cycle Regulation

Why apoptosis rather than necrosis? What are the mechanisms of apoptosis activation and cellular destruction? Intrinsic vs extrinsic activation Caspase family of proteases -- activation ‘cascade’ Intrinsic activation signals -- cell injury, P53 activation, etc -- lack of survival signal Extrinsic activation signals -- cell-surface receptors (Fas/FasL) -- cellular toxins (Granzymes) Caspase cascade Intrinsic pathway Question 18-10, p 635 Why apoptosis rather than necrosis? Cancer and Cell Cycle Regulation