The CDK Network: Linking Cycles of Cell Division and Gene Expression

Abstract

Cyclin-dependent kinases (CDKs) play essential roles in cell proliferation and gene expression. Although distinct sets of CDKs work in cell division and transcription by RNA polymerase II (Pol II), they share a CDK-activating kinase (CAK), which is itself a CDK-Cdk7-in metazoans. Thus a unitary CDK network controls and may coordinate cycles of cell division and gene expression. Recent work reveals decisive roles for Cdk7 in both pathways. The CAK function of Cdk7 helps determine timing of activation and cyclin-binding preferences of different CDKs during the cell cycle. In the transcription cycle, Cdk7 is both an effector kinase, which phosphorylates Pol II and other proteins and helps establish promoter-proximal pausing; and a CAK for Cdk9 (P-TEFb), which releases Pol II from the pause. By governing the transition from initiation to elongation, Cdk7, Cdk9 and their substrates influence expression of genes important for developmental and cell-cycle decisions, and ensure co-transcriptional maturation of Pol II transcripts. Cdk7 engaged in transcription also appears to be regulated by phosphorylation within its own activation (T) loop. Here I review recent studies of CDK regulation in cell division and gene expression, and propose a model whereby mitogenic signals trigger a cascade of CDK T-loop phosphorylation that drives cells past the restriction (R) point, when continued cell-cycle progression becomes growth factor-independent. Because R-point control is frequently deregulated in cancer, the CAK-CDK pathway is an attractive target for chemical inhibition aimed at impeding the inappropriate commitment to cell division.

Keywords: CDK-activating kinase (CAK); RNA polymerase II; cell division cycle; cyclin-dependent kinase (CDK); phosphorylation; transcription.

Figure 1.

Distinct activation pathways for different CDKs. In this model of the mammalian cell cycle, only a single CAK, Cdk7, is required, because of its ability to support distinct activation pathways for effector CDKs needed at different times. Prior to passage of the R point in G1, cell-cycle progression is reversible and dependent on continuous mitogenic signaling. Both Cdk4/cyclin D and Cdk2/cyclin E are required for R-point passage, and both might follow predominant activation pathways that are “reversible” by a cellular phosphatase (PPase). Cdk7 can overcome this opposition to activate Cdk2 by virtue of a faster rate of T-loop phosphorylation on monomeric substrates; I hypothesize a similar rate enhancement to allow activation of Cdk4/cyclin D complexes (see text; Cdk6 is omitted for clarity). Cdk2 also functions downstream of the R point, when progression through the cell cycle becomes mitogen-independent and irreversible; it has priority over Cdk1 in binding cyclin A because of its phosphorylation-first activation pathway. In the case of Cdk1, cyclin-binding and T-loop phosphorylation are mutually dependent and must occur in concert, coupled with inhibitory phosphorylations by kinases such as Wee1 and Myt1. This makes Cdk1 activation at the G2/M boundary dependent on removal of inhibitory Tyr phosphorylation by Cdc25, which is held in check by Chk1.