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Cell cycle Role of 14-3-3 proteins in cell cycle regulation

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Cell cycle Role of 14-3-3 proteins in cell cycle regulation

Role of 14-3-3 proteins in cell cycle regulation

The 14-3-3 s are a family of highly conserved proteins that play importantroles in a wide range of cellular processes including signal transduction, apoptosis,cell cycle progression, and checkpoint activation within all eukaryotic cells. These28-33 kDa helical proteins include nine isotypes ( 14-3-3 alpha, 14-3-3beta, 14-3-3 gamma, 14-3-3 delta, 14-3-3 epsilon, 14-3-3eta, 14-3-3 sigma, 14-3-3 tau and 14-3-3 zeta, with 14-3-3alpha and 14-3-3 delta being phosphorylated forms of 14-3-3 beta and14-3-3 zeta, respectively) in mammals.

14-3-3 proteins regulate the cell cycle and prevent apoptosis by controllingthe nuclear and cytoplasmic distribution of signaling molecules with which they interact.14-3-3 proteins have crucial functions during undisturbed cell divisions andseveral mechanisms involving 14-3-3 -ligand association ensure that mitosis is notprematurely activated before the completion of DNA replication in interphase [1].

14-3-3 proteins regulate the cell cycle via c ell cycle checkpoint kinase 1 (Chk1 ) [2], [3], tyrosine kinaseWee1 [4], [5], tumor suppressor p53 [6] and cyclin-dependent kinase 1 ( CDK1 ) [7].

CDC25 s are a main target for 14-3-3 -regulation. CDC25 sactivate CDK s by dephosphorylation, thus stimulating cell cycle progression. Different CDC25 s participate in different phases of cell cycle.CDC25A takes part in regulation of G1/S transition, whereas CDC25B andCDC25C regulate G2/M transition. Lack of active CDC25 s results in theaccumulation of the phosphorylated (inactive) forms of CDK s, which are incapableto participate in initiation of replication [8].

CDC25 s may be phosphorylated via ataxia telangiectasia mutated serine-proteinkinase ( ATM )/ Chk s and ataxia telangiectasia and Rad3 related proteinkinase ( ATR )/ Chk1 pathways. Chk1 is activated by 14-3-3zeta/delta with help of the checkpoint protein HUS1 [9].In addition, mitogen-activated protein kinase p38/ mitogen-activated proteinkinase-activated protein kinase 2 ( MAPKAPK2 ) pathway [10] andmitogen-activated protein kinase kinase kinase 7 ( TAK1 ) [11] mayparticipate in phosphorylation of CDC25B and CDC25C, as well.

Various isotypes of 14-3-3 proteins inhibit phosphorylated CDC25 s,which probably results in the retention of CDC25 s in the cytoplasm [3] and/or the blocked access of CDK s to the catalytic site of CDC25s [2]. Once mitosis is activated, cytoplasmic sequestration of CDC25Cby 14-3-3 proteins is inhibited by a CDK1 -mediated phosphorylation [12].

In addition, CDK1 is regulated by 14-3-3 proteins directly (by 14-3-3sigma [13] and 14-3-3 delta/zeta [5] isotypes. On the other hand,Wee1 phosphorylated by protein kinase B ( AKT ) on Ser-642 may be retainedin the cytoplasm by 14-3-3 eta [4].

It was shown that some isotypes of 14-3-3 proteins ( 14-3-3 gamma, 14-3-3tau, 14-3-3 epsilon [6] and 14-3-3 sigma [14]) may activates p53. Ionizing radiation-induced dephosphorylation ofp53 on Ser-376 is necessary for this process [6].