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Hanahan and Weinberg, Cell 144:646 (2011) The Hallmarks of Cancer.

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Presentation on theme: "Hanahan and Weinberg, Cell 144:646 (2011) The Hallmarks of Cancer."— Presentation transcript:

1 Hanahan and Weinberg, Cell 144:646 (2011) The Hallmarks of Cancer

2 Hanahan and Weinberg, Cell 144:646 (2011) Newer Hallmarks of Cancer

3 Hanahan and Weinberg, Cell 144:646 (2011) Therapeutic Targeting of the Hallmarks of Cancer

4 Cell Regulatory Networks Important in Cancer Cells Hanahan and Weinberg, Cell 100:57-70 (2000)

5 Cell Regulatory Networks Important in Cancer Cells Hanahan and Weinberg, Cell 144:646 (2011)

6 Cell cycle and its control

7 Cells must be able to proliferate - during development - wound healing - stem cells in blood, small intestine, immune system For cells to copy themselves they need to: - Grow; make more stuff; e.g. proteins, lipids - Copy their genetic material - Segregate contents to daughter cells, especially… - Segregate replicated chromosomes to daughter cells

8 Figure 8.3b The Biology of Cancer (© Garland Science 2007) START or Restriction Point INTERPHASE: G1 + S + G2

9 Cell Cycle Commandments A cell must replicate every DNA sequence once, and only once, during each cell division. A cell must not start to replicate DNA unless its mass is sufficient to support cell division. If the DNA is damaged, a cell must repair the damage before cell division. A cell must not divide until DNA replication has been completed. Each cell must receive a complete complement of replicated DNA. A cell resting in quiescence (G 0 ) must not reenter the cycle unless a proper mitogenic signal is received. A terminally differentiated cell must not reenter the cycle.

10 Figure 8.6 The Biology of Cancer (© Garland Science 2007) The Restriction Point: Integrating GO : NO-GO Signals

11 Figure 8.1 The Biology of Cancer (© Garland Science 2007) The Restriction Point: Integrating GO : NO-GO Signals

12 Two types of genes are mutated in cancer: Loss of cell cycle control at the Restriction Point tumor suppressors proto-oncogenes Activity: stimulate cell cycle progression Mutation in cancer: gain of function proto-oncogene = wt; oncogene = mutant Examples: cyclin D1, Mdm2, myc, ras Activity: Inhibit cell cycle progression Mutation in cancer: loss of function Examples: Rb, p53, p16, ARF, PTEN G0G0G0G0M G2 S G1

13 Figure 8.4 The Biology of Cancer (© Garland Science 2007) Cell Cycle Checkpoints The Guardian Mechanisms of the Genome THEY ARE DISRUPTED IN CANCER!

14 S Phase of the Cell Cycle MCM Helicase

15 During the S phase, the duplicated DNA is rearranged through cohesion to form two sister-chromatids attached to each other by cohesins The cohesins will be removed during mitosis to allow sister- chromatid separation S Phase of the Cell Cycle

16 Mitosis

17 Figure 8.3a The Biology of Cancer (© Garland Science 2007) Mitosis in Newt Lung Cells blue = DNA green = microtubules

18 At the end of the day: You need to do metaphase correctly

19 This requires organizing microtubules….

20 Kerry Bloom Kinetochore Microtubule Kinetochore Centromere Ted Salmon and attaching them to kinetochores.

21 The Metaphase to Anaphase Transition: The key step during mitosis Metaphase to anaphase transition in a plant cell

22 Figure 8.3b The Biology of Cancer (© Garland Science 2007) START or Restriction Point INTERPHASE: G1 + S + G2

23 G1-S and G2-M are the major control points in the cell cycle Rao and Johnson cell fusion experiments 1.Fuse M phase cell with interphase cell: Interphase nucleus enters M 2.Fuse S phase cell with G1 cell: The G1 nucleus enters S phase 3.Fuse S phase cell with G2 cell: The G2 nucleus does not enter S phase

24 Cyclin Dependent Kinases Regulate the Cell Cycle

25 Phosphorylation of CDK Targets Changes Their Activity Now performs a cell cycle function

26 Experimental Systems Important for Cell Cycle Studies Arbacia punctulata Xenopus laevisSchizosaccharomyces pombe Saccharomyces cerevisiae

27 Budding Yeast Saccharomyces cerevisiae

28 Lee Hartwell Hartwell was interested in the protein synthesis machinery Budding Yeast: a genetic eukaryotic model organism Let’s look for mutants that cannot synthesize proteins

29 Isolating Temperature Sensitive Mutants in Haploid Yeast

30 Lee Hartwell Serendipity: a scientist’s best friend! Brian Reid, an undergrad, needs to look at a microscope to follow a mutant. They realize that bud size stores information about the cell cycle Brian Reid

31 Permissive (low) temperatureRestrictive (high) temperature Cdc Mutants Arrest at the Same Cell Cycle Phase

32 cdc mutant growing at permissive temp (23C) cdc mutant growth arrested after 6 hrs at non-permissive temp (36C) The Behavior of a Temperature Sensitive cdc Mutant

33 How to Clone cdc Genes in Yeast

34 Cdc Genes Encode Proteins Needed for DNA Replication Studies in S. cerevisiae

35 Fission yeast: Schizosaccharomyces pombe

36 Cdc Genes Encode Proteins Needed for the G2-M Transition: Studies in S. pombe cdc2 + encodes a kinase Moreover = cdc28 in S. cerevisiae! And they can substitute for one another!!! Sir Paul Nurse

37 START (Restriction Point) Cdc2 (fission) Cdc28 (budding) Cdc2 (fission) Cdc28 (budding)

38 This is all great and yeast are really cute and interesting, but Can we really learn something from all of this about humans? Schizosaccharomyces pombe

39 Sir Paul Nurse Crazy idea Let’s try to complement (rescue) the cdc2 (-) mutant of pombe with a human cDNA library It worked for us with budding yeast genes. Why not try human genes?

40 Human cdc2 rescues cdc2 mutants!! Elongated cdc2 mutants, failing to undergo mitosis cdc2 mutants, complemented by a human cdc2 gene Melanie Lee

41 Summary - A genetic approach in fission and budding yeasts reveals genes that are essential in promoting the cells through the cell cycle -Key genes encode a protein kinase called CDKs for Cyclin-Dependent Kinases CDK1 = the protein encoded by cdc2/CDC28 What about cyclins? How were they discovered?

42 Tim Hunt Woods Hole Marine Biological Laboratory

43 Cyclin was Discovered in Sea Urchin Embryos Protein Level Time cyclin A cyclin B MMM can stimulate to lay lots of eggs

44 mitosis (Spisula is actually a clam.)

45 OK, but what does this have to do with CDK’s?? I have the answer!

46 Overview of the frog life cycle 1 mm sperm tadpole feeds, grows and becomes an adult frog OOCYTE GROWS WITHOUT DIVIDING (MONTHS) FERTILIZATION FERTILIZED EGG DIVIDES WITHOUT GROWING (HOURS)

47 The Maturation of Frog Eggs

48 An Assay for Maturation Promoting Factor (MPF) Yoshio Masui, 1971

49 MPF Activity Peaks Before Each Cell Division Moreover, MPF has kinase activity

50

51 Purification of MPF: The Birth of Cyclin Dependent Kinases This is cdc2 + !! (Cdc28 in S. cerevisiae) This is cyclin!! Which = cdc13 + in S. pombe

52 Phosphorylation of CDK Targets Changes Their Activity Now performs a cell cycle function

53 The Nobel Prize in Physiology or Medicine, 2001 “for their discovery of key regulators of the cell cycle”


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