Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms

Satyanarayana, A.; Kaldis, Philipp

doi:10.1038/onc.2009.170

Cited by 660 publications

(593 citation statements)

References 123 publications

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“…Interestingly, double knockouts of Cdk2/Cdk4 (14) and Cdk4/Cdk6 (13) but not Cdk2/Cdk6 (13) are embryonic lethal, suggesting genetic interactions. Therefore, Cdk2 and Cdk4 (as well as Cdk4 and Cdk6) display overlapping functions and can substitute for each other (3,15). In the absence of Cdk2 and Cdk4, we have demonstrated an accumulation of hypophosphorylated Retinoblastoma protein (Rb), which represses E2F-mediated transcription leading to decreased expression of E2F-target genes like Cdk1 and others (14).…”

mentioning

confidence: 94%

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Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration

Diril

Ratnacaram

Padmakumar

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

329

324

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Cyclin-dependent kinase 1 (Cdk1) is an archetypical kinase and a central regulator that drives cells through G2 phase and mitosis. Knockouts of Cdk2, Cdk3, Cdk4, or Cdk6 have resulted in viable mice, but the in vivo functions of Cdk1 have not been fully explored in mammals. Here we have generated a conditional-knockout mouse model to study the functions of Cdk1 in vivo. Ablation of Cdk1 leads to arrest of embryonic development around the blastocyst stage. Interestingly, liver-specific deletion of Cdk1 is well tolerated, and liver regeneration after partial hepatectomy is not impaired, indicating that regeneration can be driven by cell growth without cell division. The loss of Cdk1 does not affect S phase progression but results in DNA re-replication because of an increase in Cdk2/cyclin A2 activity. Unlike other Cdks, loss of Cdk1 in the liver confers complete resistance against tumorigenesis induced by activated Ras and silencing of p53.cancer | knockout mice | cell cycle regulation | polyploidy

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mentioning

confidence: 94%

“…The mammalian genome contains at least 20 different Cdks, and widespread compensation among Cdks and cyclins has been reported (2,3). Cdk1 was the first Cdk identified (4,5), is conserved in all organisms, plays important roles in mitosis, and can drive S phase in the absence of Cdk2 (6).…”

mentioning

confidence: 99%

Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration

Diril

Ratnacaram

Padmakumar

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

329

324

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“…Once activated by D-type cyclins, Cdk4/6 phosphorylate the retinoblastoma protein (pRb), leading pRb to release E2fs. E2fs are transcriptional activators that, once freed from pRb, are able to activate the transcription of genes necessary to enter S-phase [4,5]. Conversely, Cdk4/6 activity is suppressed through interactions with members of two families of inhibitory proteins: the Ink4 proteins (p15 Ink4a , p16 Ink4b , p18 Ink4c , and p19 Ink4d ) that exhibit selectivity for Cdk4/6, and the Cip/Kip proteins (p21 Cip1 , p27 Kip1 , and p57 Kip2 ) that have a broader range of Cdk inhibitory activity [6].…”

Section: Introductionmentioning

confidence: 99%

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

et al. 2011

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The presence of neurogenic precursors in the adult mammalian brain is now widely accepted, but the mechanisms coupling their proliferation with the onset of neuronal differentiation remain unknown. Here, we unravel the major contribution of the G 1 regulator cyclin-dependent kinase 6 (Cdk6) to adult neurogenesis. We found that Cdk6 was essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Specifically, Cdk6 deficiency prevents the expansion of neuronally committed precursors by lengthening G 1 phase duration, reducing concomitantly the production of newborn neurons. Altogether, our data support G 1 length as an essential regulator of the switch between proliferation and neuronal differentiation in the adult brain and Cdk6 as one intrinsic key molecular regulator of this process. STEM CELLS 2011;29:713-724 Disclosure of potential conflicts of interest is found at the end of this article.

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“…Next, it was necessary to confirm that cyclinB is the bona fide regulatory factor for cdk1-mediated phosphorylation of PR-Set7 S29, since cdk1 is known to form catalytically active complexes with other cyclins (Satyanarayana and Kaldis 2009). To this end, HeLa cells were transfected with a control shRNA or two shRNA constructs that target different regions of cyclinB (cyclinB_1 and cyclinB_2).…”

Section: S29 Is a Major Phosphorylated Residue Of Human Pr-set7mentioning

confidence: 99%

Dynamic regulation of the PR-Set7 histone methyltransferase is required for normal cell cycle progression

Wu¹,

Wang²,

Kong³

et al. 2010

Genes Dev.

125

116

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Although the PR-Set7/Set8/KMT5a histone H4 Lys 20 monomethyltransferase (H4K20me1) plays an essential role in mammalian cell cycle progression, especially during G2/M, it remained unknown how PR-Set7 itself was regulated. In this study, we discovered the mechanisms that govern the dynamic regulation of PR-Set7 during mitosis, and that perturbation of these pathways results in defective mitotic progression. First, we found that PR-Set7 is phosphorylated at Ser 29 (S29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinB complex, primarily from prophase through early anaphase, subsequent to global accumulation of H4K20me1. While S29 phosphorylation did not affect PR-Set7 methyltransferase activity, this event resulted in the removal of PR-Set7 from mitotic chromosomes. S29 phosphorylation also functions to stabilize PR-Set7 by directly inhibiting its interaction with the anaphase-promoting complex (APC), an E3 ubiquitin ligase. The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC cdh1 -mediated ubiquitination of PR-Set7 and subsequent proteolysis. This event is important for proper mitotic progression, as constitutive phosphorylation of PR-Set7 resulted in a substantial delay between metaphase and anaphase. Collectively, we elucidated the molecular mechanisms that control PR-Set7 protein levels during mitosis, and demonstrated that its orchestrated regulation is important for normal mitotic progression.[Keywords: PR-Set7; APC; Cdk1; Cdc14; cell cycle; chromatin] Supplemental material is available at http://www.genesdev.org.

show abstract

Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms

Cited by 660 publications

References 123 publications

Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration

Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

Dynamic regulation of the PR-Set7 histone methyltransferase is required for normal cell cycle progression

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