Regulation of p21WAF1/CIP1 Stability by WISp39, a Hsp90 Binding TPR Protein

Jascur, Thomas; Brickner, Howard; Salles-Passador, Isabelle; Barbier, Valérie; Khissiin, Abdelhamid El; Smith, Brian A.; Fotedar, Rati; Fotedar, Arun

doi:10.1016/j.molcel.2004.11.049

Cited by 121 publications

(127 citation statements)

References 33 publications

Supporting

Mentioning

121

Contrasting

Unclassified

Order By: Relevance

“…However, it was recently reported that p21 can be negatively regulated by MDM2 independently of any effects on p53 (Zhang Z et al, 2004b). It is therefore possible that the GA-induced p21 accumulation observed in the present study could have resulted from loss of this repressive effect, although another recent report suggests that Hsp90 plays a direct role in regulating p21 protein stability (Jascur et al, 2005).…”

Section: Discussionmentioning

confidence: 48%

Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells

et al. 2007

View full text Add to dashboard Cite

In chronic lymphocytic leukaemia (CLL), mutation/ deletion of TP53 is strongly associated with early disease progression, resistance to chemotherapy and short patient survival. Consequently, there is a pressing need to develop novel treatment protocols for this high-risk patient group. The present study was performed to evaluate Hsp90 inhibition as a possible therapeutic approach for such patients. Primary CLL cells of defined ataxia telangiectasia mutated (ATM)/p53 status were incubated with the Hsp90 inhibitor geldanamycin (GA) and analysed by western blotting for the expression of p53, p21, MDM2 and Akt. GA downregulated overexpressed mutant p53 protein (an oncogene) and upregulated wild-type (wt) p53 (a tumour suppressor). The upregulation of wt p53 by GA was independent of ATM and was accompanied by downregulation of Akt and the active form of MDM2, indicating a possible mechanism. GA also produced a p53/ ATM-independent increase in the levels of p21-a potent inducer of cell-cycle arrest. In-vitro cytotoxicity studies showed that GA killed cultured CLL cells in a dose-and time-dependent fashion irrespective of their p53/ATM status and more effectively than normal blood mononuclear cells. In summary, our findings reveal important consequences of inhibiting Hsp90 in CLL cells and strongly support the therapeutic evaluation of Hsp90 inhibitors in poor-prognosis patients with p53 defects.

show abstract

Section: Discussionmentioning

confidence: 48%

Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells

et al. 2007

View full text Add to dashboard Cite

show abstract

“…It remains to be seen whether cy1 binds one or more factors that promote Cdk2-independent degradation of p21. In addition, Wisp39 was recently identified as a factor that binds the p21 N terminus and stabilizes the p21 protein (42). It is unclear whether Cdk2 activity may influence the stabilization of p21 by Wisp39.…”

Section: Discussionmentioning

confidence: 99%

Cdk2-dependent Inhibition of p21 Stability via a C-terminal Cyclin-binding Motif

Zhu

Nie

Maki

2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

p21 is a member of the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors that includes p21, p27, and p57. Recent studies have suggested that Cdk2 activity may promote p21 degradation through a pathway similar to that for p27, although the mechanism by which this occurs has not been clarified. In the current report, co-expression with cyclin E and Cdk2 stabilized p21 in a manner that required the CDK-binding site of p21 and a cyclin-binding site (cy1) located in the p21 N terminus. Strikingly, however, a kinase-dead Cdk2 mutant stabilized p21 to a greater extent than did wild-type Cdk2, consistent with the notion that Cdk2 activity can destabilize p21. The ability of wild-type Cdk2 to destabilize p21 required a potential Cdk2 phosphorylation site in p21 at serine 130 and an intact cyclin-binding motif (cy2) in the p21 C terminus. Finally, p21 was phosphorylated by Cdk2 at Ser-130 in vitro, and this ability of Cdk2 to phosphorylate p21 was dependent, in large part, on the presence of cy2. These results support a model in which active Cdk2 destabilizes p21 via the cy2 cyclinbinding motif and p21 phosphorylation.

show abstract

“…These include a WISp39-associated chaperone pathway, 23 an SCF skp2 -dependent pathway [24][25][26] and an hdm2-dependent pathway. 27,28 Overwhelming cellular, biochemical and genetic evidence a transcriptional blockade prevented p53-induced-accumulation of p21 but not other p53 targets in S-phase RKO cells.…”

confidence: 99%