FINAL IN FOWLER A103B TUESDAY, JUNE 14 11:30 AM -- 2:30 PM POINTS FROM MIDTERM QUESTIONS POINTS FROM FINAL QUESTIONS

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INK4 CDK6 CDK2 CyclinA

Pavletich, N. P J Mol Biol. 287:821-8.

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A. A. Russo et al. Nature (1996) 382:325-31

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E2F is a transcription factor that by itself activates transcription. However, Rb binds to E2F and represses its activation function. E2F Rb

Rb repression is regulated by early G 1 Cyclins-CDKs. P P P P When Rb repression is inhibited by phosphorylation of Rb by early G 1 Cyclin-CDK protein kinases (Cyclin D-CDK4/6), E2F stimulates the expression of genes required for S-phase, including genes encoding DNA polymerases and other proteins required for DNA synthesis, enzymes that synthesize dNTPs, and genes encoding late G 1 Cyclin-CDKs (Cyclin E and CDK2) and the major S-phase Cyclin (Cyclin A).

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INK4 CDK6 CDK2 CyclinA

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Human papilloma viruses 16, 18, and 32 are initiating agents for the development of cervical carcinoma, one of the most common types of human cancers. These viruses stimulate the replication of the epidermal cells in which they replicate. Usually, this is not a problem because these lytic viruses generally kill the cells in which they replicate. But rarely, HPV DNA integrates into the DNA of a basal epidermal cell. This disrupts the viral genome so that lytic replication is blocked. However, two HPV proteins, E6 and E7 can be expressed and stimulate the cells to replicate.

The HPV E7 protein binds to Rb and displaces it from E2F. E7 Rb E2F This circumvents the function of Cyclin D-CDK4/6, promoting entry into S-phase even when Cyclin D-CDK4/6 is not activated by normal processes.

HPV E6 protein binds to p53 and another cellular protein that with E6 form a ubiquitin ligase that ubiquitinates p53. p53 Ubiquitin p53 Proteosome HPV E6 p21 CIP

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