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 stabilizationof the Cyclin D. The D-type cyclins are essential for synchronization of the cellcycle machinery with extracellular signals. [1] Expression and stability ofCyclin D is monitored by growth factor receptors [2], [3] and focal adhesion-mediated [4], [5] signalingpathways.. Expression of Cyclin D may be activated through MAPK-cascade (viaSP1 [6], c-Fos, c-Jun [7] transfactors)and/or through AKT/ IKK/ NF-KB pathway [8]. Inaddition, AKT may inhibit GSK3 beta, thus preventing degradation ofCyclin 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 CyclinD/ CDK complexes is activated by phosphorylation of CDK s by CAKcomplex [10].
CDK s inhibit retinoblastoma tumor suppressors (pRB)-family proteins ( Rbprotein, p107 and p130 ). pRB-family members are believed to functionthrough their effects on the transcription of genes regulated by the E2Ftranscription 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 induceexpression of Cyclin E, Cyclin A and some other proteins necessary for DNAreplication and the beginning of S phase. Cyclin E and Cyclin A arepositive-regulatory partners of cyclin-dependent kinase 2 ( CDK2 ). It isremarkable that both Cyclin D/ CDK4 (or CDK6 ) and CyclinE/CDK2 are necessary for induction of expression of Cyclin A [12], [13].
Activity of CDK s and Cyclines is inhibited by cell cycle kinaseinhibitors (for example, p27KIP [14] and other, see map). Duringtransition from G1 phase to S phase, p27KIP is exposed to ubiquitin-mediateddegradation by 26S proteasome [15], [16].
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