lecture 20: cell-cycle regulation and the genetics of...
TRANSCRIPT
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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