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29 Cards in this Set
- Front
- Back
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Difference between normal, immortal, and transformed cells
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Normal:
--require growth factors --arrest when confluent --require anchoring --limited proliferation --stable genome --don't form tumors in mice Immortal: --require growth factors --arrest when confluent --require anchoring --unlimited proliferation ** --less stable genome ** --don't form tumors in mice Transformed: --less dependent on growth factors --don't arrest---pile up --don't require anchoring --unlimited proliferation --unstable genome --form tumors in mice |
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How can genome instability be introduced into the cell (M phase and S phase)
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-M phase
--chromosome segregation errors in mitosis -S phase --chromosome replication errors or DNA repair defects |
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Conversion of a normal cell to a cancer cell requires how many mutations?
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-5 to 10 gene mutations in the same cell
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Conclusions of the cell fusion experiment
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- have two nuclei share the same cytoplasm even if in different cell cycle stage
-S + G1 nucleus = both to S --S nucleus releases something that drives G1 to S -S+ G2 nucleus = same --G2 nucleus resistant to S promoting factor -G1+ G2 nucleus= remain the same --no influence -Interphase + Mitosis signal= both M --mitotic nuclei relase a mitosis promoting facor (MPF) that drives all interphase nuclei into mitosis |
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What was MPF (mitosis promoting factor) found to be?
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-Found to be Cdk1 in active form when bound to Cyclin B
so MPF= Cyclin B+ Cdk1 CDK= cyclin dependent kinase |
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What levels change during the cell cycle? CDK1 or cyclin?
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-CDK levels remain the same throughout cell cycle but are inactive unless in the presence of cyclin
-cyclin levels fluctuate --high during mitosis and low during interphase |
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Cdk1 could be classified as what kind of kinase?
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- A protein serine/threonine kinase
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How does CyclinB/CDK1 promote nucear envelope disassembly? Chromosome condensation?
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-MPF phosphorylates lamin A of the nucleus, leading to disassembly
-also phosphorylates other substrates like histones, lamin B, etc --phosph of histone leads to condensing and chromosome formation |
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Why is the mitotic index for cancer cells small?
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-Because mitosis only takes up a small fraction of the cell cycle
-Even though mitosis is occuring far more often in cancer cells than in normal cells, interphase is a much longer process than mitosis |
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Mitotic rate and cancer cells
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-Cancer cells have an increased mitotic rate relative to normal cells
-mitotic rate can be the most important determinant of malignancy |
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What cell cycle transitions do cyclin-cdks govern?
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Cyclin-CDKs govern ALL of the major cell cycle transitions
-different cyclins and cdks at different phases |
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How does a substrate bind to the cyclin-CDK structure
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-substrates contact both the cyclin and the cdk subunits
-Cdk: phosphorylation target site of protein binds to CDK -Cyclin: protein binding site to cyclin |
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What determines the activity of a CDK
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-cyclins!
-inactive without cyclin -CDK2 can either govern transition from G1/S phase (cyclin E) or S/G2 phase (cyclin A) depending on which cyclin is boun |
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G0 stage =
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Quiescence, induced by contact inhibition or growth factor withdrawal
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What CDK/cyclin controls cell cycle transition from G0/G1
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Cyclin D/CDK 4
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How is cyclin D up-regulated to lead to cell cycle transition from G0 to G1
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1) mitogen activates tyrosine kinase receptor
2) Activation of PI3K and Ras pathways 3) PI3K pathway leads to cyclin D/CDK4 binding stability 4) Ras-GTP -> Raf -> Mek1/2 -> Erk 1/2 -> phosph of regulatory controls of cyclin D gene 5) leads to cyclin D transcription and upregulation PI3K = MAKE MORE STABLE RAS= MAKE MORE PROTEIN |
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Cyclin D gene and breast cancer
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-Breast cancer
--amplification of cyclin D gene (lots of copies of the gene) -cell starts progressing through G1 |
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Cyclin D is the only cyclin that responds to extracellular growth factors
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OK!
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The role of RB in progression through G1
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1) Rb binds to E2F transcription factor
2) E2F normally controls expression of S phase genes, but when bound to Rb, it is a transcriptional repressor 3) Rb-E2F recruits HDAC which prevents xscription of cell cycle progression genes |
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How does Cdk4/6 regulate Rb?
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Rb binds with E2F, the Rb-E2F complex is a transcriptional repressor
-CDK phosphorylates Rb, causing relaseing of Rb from E2F -E2F controlled xcscription can continue when Rb not bound |
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Retinoblastoma
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-what protein Rb is named after
-heterozygous for Rb mutation== 2 hit hypothesis? -Rb is mutated, probably can't bind effectively to E2F and act as a transcription repressor -3% of all childhood cancers |
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-Two hit hypothesis and retinoblastoma
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-rare to spontaneosly mutate both normal Rb gene copies
--1 in 30k chance -more likely that it is second hit: individual already carries one mutant gene and the normal copy sporadically mutates --most individuals w inherited mutation develop retinal tumors |
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Tumor suppressors
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-inhibit cell cycle progression
-mutation in cancer= loss of function -Examples are Rb, p53, p16, ARF |
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Proto-oncogenes
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-stimulate cell cycle profession
-mutation in cancer: gain of function leading to oncogene --ie proto= wt and onco= mutant -Examples are cyclin D1, Mdm2, myc, ras |
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What happens if cyclin D is overexpressed in a cancer cell?
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-over- phosphorylation of Rb, so Rb dissociates from E2F and is no longer a transcriptional repressor
-a proto-oncogene turned oncogene |
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What happens if Rb is mutated in cancer cells?
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-Rb can't bind effectively to E2F, can't be a transcriptional repressor
-loss of function in a tumor supressor |
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A cell must no start to replicate DNA unless its mass is sufficient to support the replication
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-Cell growth occurs in G1
-cell too small, will divide into two abnormally small cells |
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C-myc
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- a transcription factor that controls cell growth
-when phosph and active, promotes transcription of protein synthesis genes -a proto-oncogene -overexpressed or hyperactive in many leukemias and lymphomas -helps cell move from G0 to G1 to S by getting cell to big enough mass for replication |
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How is c-myc activity up-regulated in cells?
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-through tyrosine kinase receptor activity and activity of Ras and PI3K pathway that lead to phosphorylation of c-myc
-phopsh of c-myc leads to active form ---> transcription factor leads to xscription of protein synthesis genes |
