Phosphorylation of the Cyclin-Dependent Kinase Inhibitor p21Cip1 on Serine 130 Is Essential for Viral Cyclin-Mediated Bypass of a p21Cip1-Imposed G1 Arrest

Järviluoma, Annika; Child, Emma S.; Sarek, Grzegorz; Sirimongkolkasem, Papinya; Peters, Gordon; Ojala, Päivi M.; Mann, David J.

doi:10.1128/mcb.26.6.2430-2440.2006

Cited by 45 publications

(48 citation statements)

References 39 publications

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“…KSHV also expresses a viral cyclin (K-cyclin) with functional properties of cellular D-and E-type cyclins (7,43). K-cyclin is resistant to inhibition by p21 and induces the phosphorylation of p21 at serine 130, resulting in the inactivation of p21 (7,20,40). We have independently confirmed that mutation of p21 serine 130 to alanine results in a p21 mutant protein that is a more potent inhibitor of cell cycle progression in BC-3 cells than wt p21 (data not shown).…”

Section: Resultsmentioning

confidence: 99%

A Human Herpesvirus MicroRNA Inhibits p21 Expression and Attenuates p21-Mediated Cell Cycle Arrest

Gottwein

Cullen

2010

J Virol

149

128

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The oncogenic human gammaherpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) expresses 12 viral microRNAs (miRNAs) in latently infected cells. Here, we report that cellular mRNAs encoding the cellular cyclin-dependent kinase inhibitor p21, a key inducer of cell cycle arrest, are direct targets for KSHV miR-K1. Ectopically expressed KSHV miR-K1 specifically inhibited the expression of endogenous p21 in KSHV-negative cells and strongly attenuated the cell cycle arrest that normally occurs upon p53 activation, yet miR-K1 did not prevent the induction of other p53-responsive genes. Stable knockdown of miR-K1 in latently KSHV-infected human primary effusion lymphoma (PEL) B cells revealed a derepression of p21 expression and enhanced cell cycle arrest following activation of p53. Our data demonstrate that miR-K1 represses the expression of p21, a protein with known tumor suppressor functions, and suggest that this KSHV miRNA is likely to contribute to the oncogenic potential of this opportunistic viral pathogen.

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Section: Resultsmentioning

confidence: 99%

A Human Herpesvirus MicroRNA Inhibits p21 Expression and Attenuates p21-Mediated Cell Cycle Arrest

Gottwein

Cullen

2010

J Virol

149

128

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“…Phosphorylation at S130 was reported to either stabilize p21 (29) or promote its degradation (3,67). This modification was also proposed to cause p21 inactivation that was not attributed to degradation, but rather caused by its loss of cyclin/Cdk2 association (26). The p21 phosphorylation sites described above are conserved in both mice and humans.…”

Section: Kip2mentioning

confidence: 99%

Cdk2-dependent phosphorylation of p21 regulates the role of Cdk2 in cisplatin cytotoxicity

Hodeify

Tarcsafalvi

Megyesi

et al. 2011

American Journal of Physiology-Renal Physiology

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Hodeify R, Tarcsafalvi A, Megyesi J, Safirstein RL, Price PM. Cdk2-dependent phosphorylation of p21 regulates the role of Cdk2 in cisplatin cytotoxicity. Am J Physiol Renal Physiol 300: F1171-F1179, 2011. First published February 16, 2011 doi:10.1152/ajprenal.00507.2010.-Cisplatin cytotoxicity is dependent on cyclin-dependent kinase 2 (Cdk2) activity in vivo and in vitro. We found that an 18-kDa protein identified by mass spectrometry as p21 WAF1/Cip1 was phosphorylated by Cdk2 starting 12 h after cisplatin exposure. The analysis showed it was phosphorylated at serine 78, a site not previously identified. The adenoviral transduction of p21 before cisplatin exposure protects from cytotoxicity by inhibiting Cdk2. Although cisplatin causes induction of endogenous p21, the protection is inefficient. We hypothesized that phosphorylation of p21 at serine 78 could affect its role as a Cdk inhibitor, and thereby lessen its ability to protect from cisplatin cytotoxicity. To investigate the effect of serine 78 phosphorylation on p21 activity, we replaced serine 78 with aspartic acid, creating the phosphomimic p21 S78D . Mutant p21 S78D was an inefficient inhibitor of Cdk2 and was inefficient at protecting TKPTS cells from cisplatininduced cell death. We conclude that phosphorylation of p21 by Cdk2 limits the effectiveness of p21 to inhibit Cdk2, which is the mechanism for continued cisplatin cytotoxicity even after the induction of a protective protein.cell death CISPLATIN IS A CHEMOTHERAPEUTIC drug used as a first-line component in the treatment of several solid tumors, including testicular, head and neck, and ovarian and cervical cancers (14). Its dosage and efficacy are limited by its side effects, especially nephrotoxicity (39). Cisplatin cytotoxicity in kidney cells is dependent on cyclin-dependent kinase 2 (Cdk2) activity in vivo and in vitro (42,43). This dependence was shown by Cdk2 inhibitory drugs, dominant-negative Cdk2 transduction, and expression of the cyclin-dependent kinase inhibitor (CDKI), p21, all of which protected from cisplatininduced cell death. Cdk2 is a serine/threonine protein kinase, whose main described function is the phosphorylation of substrates necessary for cell cycle progression (37). The Cdk2 pathways involved in cisplatin-induced cell death are not yet understood, and one substrate in these pathways is described below.Cdk2 activity is regulated by several mechanisms, including binding to cyclins, positive and negative phosphorylation, and binding of CDKIs (38). Apart from its role in cell cycle progression, various studies showed increased Cdk2 activity associated with programmed cell death (apoptosis) (21,36,43,45,54,65,66), and inhibition of Cdk2 activity in vitro has been shown to protect cultured cells from apoptosis (40,42,43,61).In the present study, we identified a Cdk2 substrate induced after cisplatin exposure. An 18-kDa protein accumulated and was phosphorylated by Cdk2 starting 12 h after cisplatin exposure, which coincided with the time when Cdk2 inhibition no longer protec...

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“…21). Additionally phosphorylation of p21 on S130 (22) or T145 (23) negates its inhibition of cyclin/cdks and results in the restoration of cdk2 kinase activity in the presence of p21, as well as cell proliferation. These data suggest that modifications of p21 may change its functional activity.…”

Section: P21mentioning

confidence: 99%

Is p21 an oncogene?

Gartel

2006

Molecular Cancer Therapeutics

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Phosphorylation of the Cyclin-Dependent Kinase Inhibitor p21^Cip1 on Serine 130 Is Essential for Viral Cyclin-Mediated Bypass of a p21^Cip1-Imposed G₁ Arrest

Cited by 45 publications

References 39 publications

A Human Herpesvirus MicroRNA Inhibits p21 Expression and Attenuates p21-Mediated Cell Cycle Arrest

A Human Herpesvirus MicroRNA Inhibits p21 Expression and Attenuates p21-Mediated Cell Cycle Arrest

Cdk2-dependent phosphorylation of p21 regulates the role of Cdk2 in cisplatin cytotoxicity

Is p21 an oncogene?

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