Cell cycle - Regulation of G1/S transition (part 2)

Regulation of G1/S transition (part 2)

The commencement of the cell cycle coincides with the production and the stabilization of the Cyclin D. The D-type cyclins are essential for synchronization of the cell cycle machinery with extracellular signals. [1] Expression and stability of Cyclin D is monitored by growth factor receptors [2], [3] and focal adhesion-mediated [4], [5] signaling pathways.. Expression of Cyclin D may be activated through MAPK-cascade (via SP1 [6], c-Fos, c-Jun [7] transfactors) and/or through AKT / IKK / NF-KB pathway [8]. In addition, AKT may inhibit GSK3 beta, thus preventing degradation of Cyclin D via the GSK3-dependent pathway [9].

Cyclins D are positive-regulatory partners of cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6). Accumulating of Cyclin D/CDK complexes is activated by phosphorylation of CDKs by CAK complex [10].

CDKs inhibit retinoblastoma tumor suppressors (pRB)-family proteins (Rb protein, p107 and p130). pRB-family members are believed to function through their effects on the transcription of genes regulated by the E2F transcription factors. CDK4 or CDK6 phosphorylate pRB-family members, thereby liberating E2Fs (for example, E2F1 or E2F4) [11]. These transcription factors associate with DP1 and together they induce expression of Cyclin E, Cyclin A and some other proteins necessary for DNA replication and the beginning of S phase. Cyclin E and Cyclin A are positive-regulatory partners of cyclin-dependent kinase 2 (CDK2). It is remarkable that both Cyclin D/CDK4 (or CDK6) and Cyclin E/CDK2 are necessary for induction of expression of Cyclin A [12], [13].

Activity of CDKs and Cyclines is inhibited by cell cycle kinase inhibitors (for example, p27KIP [14] and other, see map). During transition from G1 phase to S phase, p27KIP is exposed to ubiquitin-mediated degradation by 26S proteasome [15], [16].

References:

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