Role of 14-3-3 proteins in cell cycle
The 14-3-3s are a family of highly conserved proteins
that play important roles in a wide range of cellular processes including signal
transduction, apoptosis, cell cycle progression, and checkpoint activation within all
eukaryotic cells. These 28-33 kDa helical proteins include nine isotypes
(14-3-3 alpha, 14-3-3 beta,
14-3-3 gamma, 14-3-3 delta,
14-3-3 epsilon, 14-3-3 eta,
14-3-3 sigma, 14-3-3 tau and
14-3-3 zeta, with 14-3-3 alpha
and 14-3-3 delta being phosphorylated forms of
14-3-3 beta and 14-3-3 zeta,
respectively) in mammals.
14-3-3 proteins regulate the cell cycle and prevent
apoptosis by controlling the nuclear and cytoplasmic distribution of signaling molecules
with which they interact. 14-3-3 proteins have crucial
functions during undisturbed cell divisions and several mechanisms involving
14-3-3-ligand association ensure that mitosis is not
prematurely activated before the completion of DNA replication in interphase .
14-3-3 proteins regulate the cell cycle via cell cycle
checkpoint kinase 1
(Chk1) , and by phosphorylation of cell division cycle 25 phosphatases
(CDC25s) , ,
tyrosine kinase Wee1 , ,
tumor suppressor p53  and cyclin-dependent
kinase 1 (CDK1) .
CDC25s are a main target for
activate CDKs by dephosphorylation, thus stimulating cell
cycle progression. Different
CDC25s participate in different
phases of cell cycle. CDC25A takes part in regulation of
G1/S transition, whereas CDC25B and CDC25C
regulate G2/M transition. Lack of active
CDC25s results in the accumulation of the phosphorylated
(inactive) forms of CDKs, which are incapable to participate
in initiation of replication .
CDC25s may be phosphorylated via ataxia telangiectasia
mutated serine-protein kinase
and ataxia telangiectasia and Rad3 related
pathways. Chk1 is activated by 14-3-3
zeta/delta with help of the checkpoint
protein HUS1 . In addition,
mitogen-activated protein kinase p38 / mitogen-activated
protein kinase-activated protein kinase 2 (MAPKAPK2) pathway
 and mitogen-activated protein kinase kinase kinase 7
(TAK1)  may participate in
phosphorylation of CDC25B and
CDC25C, as well.
Various isotypes of 14-3-3 proteins inhibit
phosphorylated CDC25s, which probably results in the
retention of CDC25s in the cytoplasm  and/or
the blocked access of CDKs to the catalytic site of
CDC25s . Once mitosis is activated,
cytoplasmic sequestration of CDC25C by
14-3-3 proteins is inhibited by a
CDK1-mediated phosphorylation .
In addition, CDK1 is regulated by
14-3-3 proteins directly (by 14-3-3 sigma
) or via Wee1.
Active Wee1 inhibits Cdk1 by
Tyr15 phosphorylation. Wee1 may be activated by
14-3-3 alpha/beta  and 14-3-3
delta/zeta  isotypes. On the other hand,
by protein kinase B
(AKT) on Ser-642
may be retained in the cytoplasm by 14-3-3 eta .
It was shown that some isotypes of 14-3-3 proteins (14-3-3
gamma, 14-3-3 tau, 14-3-3
epsilon  and 14-3-3 sigma
) may activates p53. Ionizing
radiation-induced dephosphorylation of p53 on Ser-376 is
necessary for this process .
- Brunet A, Kanai F, Stehn J, Xu J, Sarbassova D, Frangioni JV, Dalal SN, DeCaprio JA, Greenberg ME, Yaffe MB
14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport.
The Journal of cell biology 2002 Mar 4;156(5):817-28
- Jiang K, Pereira E, Maxfield M, Russell B, Goudelock DM, Sanchez Y
Regulation of Chk1 includes chromatin association and 14-3-3 binding following phosphorylation on Ser-345.
The Journal of biological chemistry 2003 Jul 4;278(27):25207-17
- Forrest A, Gabrielli B
Cdc25B activity is regulated by 14-3-3.
Oncogene 2001 Jul 19;20(32):4393-401
- Dalal SN, Yaffe MB, DeCaprio JA
14-3-3 family members act coordinately to regulate mitotic progression.
Cell cycle (Georgetown, Tex.) 2004 May;3(5):672-7
- Katayama K, Fujita N, Tsuruo T
Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promote cell cycle progression at G2/M transition.
Molecular and cellular biology 2005 Jul;25(13):5725-37
- Rothblum-Oviatt CJ, Ryan CE, Piwnica-Worms H
14-3-3 binding regulates catalytic activity of human Wee1 kinase.
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 2001 Dec;12(12):581-9
- Stavridi ES, Chehab NH, Malikzay A, Halazonetis TD
Substitutions that compromise the ionizing radiation-induced association of p53 with 14-3-3 proteins also compromise the ability of p53 to induce cell cycle arrest.
Cancer research 2001 Oct 1;61(19):7030-3
- Samuel T, Weber HO, Rauch P, Verdoodt B, Eppel JT, McShea A, Hermeking H, Funk JO
The G2/M regulator 14-3-3sigma prevents apoptosis through sequestration of Bax.
The Journal of biological chemistry 2001 Nov 30;276(48):45201-6
- Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S
Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints.
Annual review of biochemistry 2004;73:39-85
- Manke IA, Nguyen A, Lim D, Stewart MQ, Elia AE, Yaffe MB
MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation.
Molecular cell 2005 Jan 7;17(1):37-48
- Peng CY, Graves PR, Ogg S, Thoma RS, Byrnes MJ 3rd, Wu Z, Stephenson MT, Piwnica-Worms H
C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding.
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 1998 Mar;9(3):197-208
- Bulavin DV, Higashimoto Y, Demidenko ZN, Meek S, Graves P, Phillips C, Zhao H, Moody SA, Appella E, Piwnica-Worms H, Fornace AJ Jr
Dual phosphorylation controls Cdc25 phosphatases and mitotic entry.
Nature cell biology 2003 Jun;5(6):545-51
- Wang Y, Jacobs C, Hook KE, Duan H, Booher RN, Sun Y
Binding of 14-3-3beta to the carboxyl terminus of Wee1 increases Wee1 stability, kinase activity, and G2-M cell population.
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 2000 Apr;11(4):211-9
- Mhawech P
14-3-3 proteins--an update.
Cell research 2005 Apr;15(4):228-36