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The Biology of Cancer Chapter 8: pRb and Control of the
Robert A. Weinberg The Biology of Cancer First Edition Chapter 8: pRb and Control of the Cell Cycle Clock Copyright © Garland Science 2007
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Cell cycle clock is the master governor to decide proliferation or not
Figure 8.1 The Biology of Cancer (© Garland Science 2007)
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Chromosomal instability (genomic instability) is one of hallmark of cancers
Figure 8.5a The Biology of Cancer (© Garland Science 2007)
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Cells make decision about growth and quiescence during a specific period in the G1 stage
Figure 8.6 The Biology of Cancer (© Garland Science 2007)
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The Cell cycle system, three major euk systems;
in yeast, frog, mammalian cells Yeast; Fission ( S. pombe) and budding yeast ( S. cerevisiae) - genetically useful; genetic manipulation Haploid state Cdc genes; cell-division cycle genes; ts mutant (permissive or restrictive condition *No nuclear envelop breakage during mitosis * budding yeast; no clear G2 phase
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Isolation of wild-type cell-division cycle (CDC) genes from S
Isolation of wild-type cell-division cycle (CDC) genes from S. cerevisiae carrying temperature-sensitive mutations in these genes Figure 13-4
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Two classes of mutations in S
Two classes of mutations in S. pombe produce either elongated or very small cells S. pombe Cdc2-Cdc13 heterodimer is equivalent to Xenopus MPF (Cdc2 is cdk, Cdc13 is cyclin B) Figure 13-11
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MPF promotes maturation of Xenopus laevis oocytes
Figure 13-5
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MPF promotes mitosis in somatic cells
Figure 13-6
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Cell cycle-dependent fluctuations in the cyclin B levels
Cyclin B levels and MPF activity change together in cycling Xenopus egg extracts, MPF is a dimer of a mitotic cyclin and cyclin-dependent kinase (cdk) Figure 8.9 The Biology of Cancer (© Garland Science 2007)
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Ossilation of cyclin levels during the cell cycle
Figure The Biology of Cancer (© Garland Science 2007)
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Cyclins and Cdk constitute the core components of the cell cycle clock
Figure 8.7 The Biology of Cancer (© Garland Science 2007)
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Components of the cell cycle control system
*The control of cell cycle regulation; a clock or timer; specific time -correct order-once per cycle -binary switch on/off system -adaptability; specific cell types or environmental Checkpoint control; delay the cell cycle progression or arrest the cell cycle in response to signals -send a negative signal rather than removal of positive signal -provide time for DNA repair or prevent the disaster
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-Cyclin-dependent kinase (Cdks)
The cell cycle regulation are based on cyclically activated protein kinase; Multiple cdks and cyclins regulate passage of mammalian cells through the cell cycle -Cyclin-dependent kinase (Cdks) -cdk regulators; *different cyclins, *level of cyclins (transcriptionally or proteolysis), * inhibitors (p21, 27, p16, p57 etc) * phosphorylation or dephosphorylation (Cdc25, kinase)
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Cdk activity are regulated by inhibitory phosphorylation and by CIPs
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The cell cycle control system depends cyclical proteolysis; SCF, APC
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Mitogenic signaling increase the level of cylin D
Figure 8.11b The Biology of Cancer (© Garland Science 2007)
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Control of cyclin levels during the cell cycle and Cdk are also regulated by CdkIs
Figure The Biology of Cancer (© Garland Science 2007)
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Control of cell cycle progression by various mitogenic signals
Inhibitory signal TGF-beta induce the p15 CDKI Stimulatory signal Figure 8.14a The Biology of Cancer (© Garland Science 2007)
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Suppression of p27 function by Akt/PKB in human breast cancer
Nuclear P27 Figure 8.16a The Biology of Cancer (© Garland Science 2007)
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Interaction of CDK Is with Cylin-Cdks;
P27,p21 differentially affect the Cdks activity p21, p27 stimulate Cdk4/6 at early G1, but inhibit Cdk2 from late G1-to M
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The level of p27 is elevated in the post-mitotic cells or differentiated cells
Brdu p27 Non-dividing granule cells of the cerebellum Figure 8.18a The Biology of Cancer (© Garland Science 2007)
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Cell cycle phosphorylation of Rb; Rb is the determinant of R point
(Active Rb) (Inactive Rb) Figure The Biology of Cancer (© Garland Science 2007)
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Rb bind to and inhibit E2F TFs
Figure 8.23a The Biology of Cancer (© Garland Science 2007)
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E2F TFs function as activator or repressor
Figure 8.23d The Biology of Cancer (© Garland Science 2007)
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Structure of Rb and E2F Figure 8.23b The Biology of Cancer (© Garland Science 2007)
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Modification of chromatin by Rb
Figure 8.24a The Biology of Cancer (© Garland Science 2007)
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Positive feedback loops and the irreversible of cell cycle progression
Cdk2 Rb E2F E-Cdk2 p27 Figure 8.25a The Biology of Cancer (© Garland Science 2007)
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Counterbalancing the level of Cyclin D by several mitogenic signaling
G1-S progression Figure The Biology of Cancer (© Garland Science 2007)
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Myc : bHLH TF, contributes to the cell differentiation and cell cycle progression
Figure The Biology of Cancer (© Garland Science 2007)
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Oncogenic activity of Myc overexpression
Many Myc-binding sites of targets Figure The Biology of Cancer (© Garland Science 2007)
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Table 8.2 The Biology of Cancer (© Garland Science 2007)
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How TGF-beta blocks the cell cycle progression
Figure The Biology of Cancer (© Garland Science 2007)
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Viral oncoprotein inhibit the Rb by direct binding;
E1A, T-Ag are sequestering and inactivating Rb E7 tags Rb for its ubiquitination and destruction Figure The Biology of Cancer (© Garland Science 2007)
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Rb also control the differentiation
Myoblasts only differentiate after proliferation stops. When growth factors are present, MyoD & Myf-5 are expressed and the myoblasts proliferate & do not differentiate. Removal of growth factors causes myoblasts to withdraw from the cell cycle; fusion and differentiation follow. The retinoblastoma protein (Rb) can block cell growth and is inactivated by phosphorylation in proliferating cells. Dephosphorylation of Rb & blockage of cell cycle is a "differentiation decision". Cdk phosphorylate MyoD and promotes its destruction Id binds to and sequest Rb and promote cell cycle progression, If Id is overexoressed ? What happen?
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Table 8.3 The Biology of Cancer (© Garland Science 2007)
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Table 8.4 The Biology of Cancer (© Garland Science 2007)
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Figure 8.35 The Biology of Cancer (© Garland Science 2007)
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Amplification of cyclin D in cancer cells
Figure The Biology of Cancer (© Garland Science 2007)
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Suppression of p27,free Cyclin E, Rb by Skp2
Figure 8.37a The Biology of Cancer (© Garland Science 2007)
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Figure 8.37d The Biology of Cancer (© Garland Science 2007)
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Figure 8.38 The Biology of Cancer (© Garland Science 2007)
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