Pathway maps

Cell cycle_Regulation of G1/S transition (part 2)
Cell cycle_Regulation of G1/S transition (part 2)

Object List (links open in MetaCore):

Cyclin D, c-Fos, Rb protein, Erk (MAPK1/3), IKK-alpha, DP1, SP1, E2F4/DP1 complex, E2F1, p130, CDK2, CDK4, Cyclin D2, RelA (p65 NF-kB subunit), CDK6, Cyclin A, GSK3 beta, Cyclin E, p107, c-Jun, E2F1/DP1 complex, AKT(PKB), E2F4, Cyclin D1, CAK complex, Cyclin D3


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 CDK s by CAK complex [10].

CDK s 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 CDK s 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].


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