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Cell cycle Regulation of G1/S transition (part 1)


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Cell cycle Regulation of G1/S transition (part 1)

Regulation of G1/S transition (part 1)

DNA damage checkpoints are biochemical pathways that delay or halt cell cycleprogression in response to DNA damage. Cell cycle proceeds in four phases in all somaticeukaryotic cells, G1, S, G2, and M, and one outside the cycle per se, G0 [1].

The G1/S cell cycle checkpoint controls the passage of q cell from the first 'gap'phase (G1) into the DNA synthesis phase (S). Many different stimuli exert G1/S checkpointcontrol, including TGF-beta, DNA damage, contact inhibition, replicative senescence, andgrowth factor withdrawal.

Transforming growth factor-beta 1 ( TGF-beta 1 ) [2] andtransforming growth factor-beta 2 ( TGF-beta 2 ) [3] participate inregulation of the G1/S checkpoint. TGF-beta signals are transmitted by contactingtwo distantly related transmembrane serine/threonine kinases, named receptors I ( TGFreceptor I ) and II ( TGF receptor II ). TGF-beta 1 and/or TGF-beta2 bind directly to TGF receptor II, which is a constitutively active kinase.The bound TGF-beta factors are then recognized by TGF receptor I, which isrecruited into the complex and becomes phosphorylated by TGF receptor II.Phosphorylation allows TGF receptor I to propagate the signal to downstreamsubstrates [4].

TGF-beta signaling leads to an excitation of at least two pathways.

TGF-beta factors induce an association of its receptor with regulatory subunitof protein phosphatase-2A ( PP2A ). Concomitantly, three PP2A subunits(regulatory, structural and catalytic) lead to dephosphorylation and inactivation ofribosomal protein S6 kinase, 70kD, polypeptide 1 ( p70 kinase 1 ) [5]. Inactivated p70 kinase 1 fails to oppress activity of glycogen synthasekinase 3 beta ( GSK3 beta ). In this case, GSK3 beta phosphorylatescyclin D, making it accessible to the subsequent ubiquitination and proteosomaldegradation [6]. Stimulation of GSK3 beta activity is observed also inthe case of growth factor withdrawal [7].

In addition, TGF receptor I activates by phosphorylation SMAD family member 2and 3 ( Smad2 and Smad3 ), which form complexes with SMAD family member 4 (Smad4 ) that accumulate in the nucleus and regulate transcription of target genes[8]. Smad s stimulate transcription of proteins from INK4 (p16INK and p15 ) and Kip/Cip ( p21 and p27KIP1 ) families ofcell cycle kinase inhibitors directly or indirectly (for example, via b-Jun andSP1 transfactors). These inhibitors interfere with interactions betweencyclin-dependent kinases ( CDK ) and cyclin s. Contact inhibition [9], replicative senescence [10], [11] and DNA damage[1] also may stimulate the G1/S checkpoint arrest through p15,p21 or p27KIP1.

Moreover, DNA damage leads to phosphorylation of checkpoint homologues ( Chk ).Phosphorylated Chk, in turn, inactivates by phosphorylation cell division cycle25A phosphatase ( Cdc25A ). Lack of active Cdc25A results in theaccumulation of the phosphorylated (inactive) form of Cdk2 and Cdk4, whichare incapable to participate in initiation of replication [1].

Phosphorylated CDC25A may be exposed to ubiquitination by Anaphase-promotingcomplex ( APC ) and/or SCF E3 ubiquitin ligase complex in Smad3-dependent manner (with following proteosomal degradation) [12].

Polo-like kinase 3 ( PLK3 ) may stimulate G1/S transition, e.g., via activationof CDC25A [13], [14].