G0

When G0 mammalian cells are stimulated with mitogens, receptor tyrosine kinases transduce signals to activate immediate early transcription factors such as c-Fos and c-Jun, causing expression of the D-type cyclins, the E2F family of transcription factors, and other early genes required for progression through G1.1-3 The activities of these early gene products ultimately control the passage of the cell through the restriction point and into the cell cycle. During G1, E2F family transcription factors are bound by the retinoblastoma protein, pRb, which converts E2F from a transcriptional activator to a transcriptional repressor via its association with histone deacetylase complexes. As cyclin D levels rise through G1 in response to mitogenic stimuli, the cyclin forms an active cyclin-cdk complex with either of the two related D-type cyclin cdks, Cdk4 or Cdk6; these active kinase complexes drive the cell through the restriction point by phosphorylat-ing pRb, allowing E2F to activate transcription of cyclin E (Figure 16.2). As the amount of cyclin D-Cdk complex increases, it acts as a sink for the Cip/Kip family of cdk inhibitors.4

The Cip/Kip inhibitors, including p21, p27, and p57, act as potent inhibitors of cyclin E/Cdk2 activity. Cyclin D-Cdk complexes contribute to increasing cyclin E/Cdk2 activity through E2F-mediated transcription as well as the sequestra-

CIP/KIP proteins I

y Cyclin E

Wee1 CAK.

| Cdc25A Wee1

INK4A proteins

CdK2

┬▒CAK, jfCdc25k

Cyclin A Cdfc2

Weel

CIP/KIP proteins I

y Cyclin E

CdK2

Weel

Cyclin B Cdk1

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