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Lecture 20: Cell-Cycle Regulation and theGenetics of Cancer

Read chapter 15.1-6(642-675)

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The normal cell division

The cell cycle hasfour phases:G1, S G2, and M

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Isolation of temperature-sensitivemutants in yeast

• Mutants grow normally atpermissive temperature

• Mutants loses genefunction at restrictivetemperature

• Thousands of cell cyclemutants have beenidentified

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A cell-cycle mutant in yeast

• (a) growth at permissivetemperature displays buds ofall sizes

• (b) growth at restrictivetemperature shows cells havefinished first cell cycle andarrested in the second

Fig. 15.6

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Use of heat-sensitive mutations to decipherthe timing of a gene’s function in the cell cycle

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Cyclin-dependent kinases (CDK) control thecell cycle by phosphorylating other proteins

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Nuclear lamins are one of the substrates of CDK

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Three cell cycle check points ensure genomic stability

G1 to S (start) check pointsG2 to M check pointsMetaphase-anaphase check points

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CDKs mediate the transition from the G1-to-S phase in human cells

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Interactions between various tumor suppressorsand proto-oncogenes in growth control of a cell

Fig. 15.24

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70 cell-cycle genes identified throughtemperature-sensitive mutation screens

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-members of Li-Fraumeni cancer-prone families wereshown to carry germ-line p53 mutations.-mice that are homozygous null for p53 are highlypredisposed to tumors.

p53: an anti-oncogenic protein

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Fig. 18.11 a

p53

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Over 50% cancer cells contain mutations in p53

Fig. 18.11 c,d

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G2-to-M check points

Fig. 18.10

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G2-to-M check points

Fig. 18.12a

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Metaphase to anaphase checkpoint

Fig. 18.12b

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General cancer phenotype includesmany types of cellular abnormalities

• Autocrine stimulation –tumor cells make their ownsignals to divide

• Loss of contact inhibition –lost property to stopdividing when contactedby another cell

• Loss of cell death –resistance to programmedcell death

• Loss of gap junctions – nochannels for connecting toneighbor cell

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Three classes of error lead toaneuploidy in tumor cells

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Changes that enable tumor to disrupt localtissue and invade distant tissues

• Ability to metastasize• Angiogenesis – secrete substances that cause blood vessels to grow

toward tumor• Evasion of immune surveillance

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A. Cancer phenotype results fromaccumulation of multiple mutations in theclonal progeny of cells

B. Most cancers result from exposures tomutagens

• If one sib or twin gets cancer, other usually does not• Populations that migrate – profile of cancer becomes

more like people indigenous to new location

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Cancer develops over time

Fig. 18.19

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Cancer arises by successive mutations in aclone of proliferating cells

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Cancer mutations occur in two forms

• Oncogenes– dominant

mutations• Mutant tumor-

suppressor genes– recessive

mutations

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Oncogenes

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• Exposure of noncancerouscells to tumor DNA inculture– Human tumor DNA to

transform normal mousecells

– Human DNA isolatedfrom transformants

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Tumor suppressor genes

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Some cancers run in families such asretinoblastoma