Hsp90 Regulates the Activity of Wild Type p53 under Physiological and Elevated Temperatures

Müller, L.; Schaupp, Andreas; Walerych, Dawid; Wegele, Harald; Büchner, Johannes

doi:10.1074/jbc.m407687200

Cited by 134 publications

(130 citation statements)

References 68 publications

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“…Although wt p53 has also been reported as an Hsp90 client protein (Wang and Chen, 2003;Muller et al, 2004;Walerych et al, 2004), our demonstration that GA increased rather than decreased the levels of wt p53 suggests that this is not the case in CLL cells. Instead, our data are more in keeping with the idea that Hsp90 inhibition depletes Akt, which in turn results in loss of MDM2 function and consequent derepression of wt p53.…”

Section: Discussioncontrasting

confidence: 58%

“…Thus in other cell types, wt p53 (Wang and Chen, 2003;Muller et al, 2004;Walerych et al, 2004), mutant p53 (Blagosklonny et al, 1996;Sepehrnia et al, 1996;Whitesell et al, 1998;Nagata et al, 1999) and Akt (Sato et al, 2000;Basso et al, 2002;Fujita et al, 2002) have each been implicated as Hsp90 client proteins. Akt can potentially suppress the function of wt p53 by phosphorylating and activating its inhibitory partner, MDM2 (Vogelstein et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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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

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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.

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Section: Discussioncontrasting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

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

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“…In vitro wt p53 can interact with Hsp40 and Hsp70, but such a complex is dissociated in the presence of Hsp90 (46). Transient interaction of p53 with Hsp90 is required for p53 binding to its consensus promoter DNA sequence (29,36). When p53 is in a complex with a promoter sequence, it is no longer in a complex with Hsp90.…”

Section: Discussionmentioning

confidence: 99%

MDM2 Chaperones the p53 Tumor Suppressor

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Wallace

et al. 2007

Journal of Biological Chemistry

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The murine double minute (mdm2) gene encodes an E3 ubiquitin ligase that plays a key role in the degradation of p53 tumor suppressor protein. Nevertheless recent data highlight other p53-independent functions of MDM2. Given that MDM2 protein binds ATP, can interact with the Hsp90 chaperone, plays a role in the modulation of transcription factors and protection and activation of DNA polymerases, and is involved in ribosome assembly and nascent p53 protein biosynthesis, we have evaluated and found MDM2 protein to possess an intrinsic molecular chaperone activity. MDM2 can substitute for the Hsp90 molecular chaperone in promoting binding of p53 to the p21-derived promoter sequence. This reaction is driven by recycling of MDM2 from the p53 complex, triggered by binding of ATP to MDM2. The ATP binding mutant MDM2 protein (K454A) lacks the chaperone activity both in vivo and in vitro. Mdm2 cotransfected in the H1299 cell line with wild-type p53 stimulates efficient p53 folding in vivo but at the same time accelerates the degradation of p53. MDM2 in which one of the Zn 2؉ coordinating residues is mutated (C478S or C464A) blocks degradation but enhances folding of p53. This is the first demonstration that MDM2 possesses an intrinsic molecular chaperone activity, indicating that the ATP binding function of MDM2 can mediate its chaperone function toward the p53 tumor suppressor.The p53 tumor suppressor gene encodes a sequence-specific transcription factor that is mutated in the vast majority of human cancers (1). Two other paralogs of p53, namely p63 and p73, have been identified, but the physiological functions of each member of the p53 family appear to be rather distinct (for review, see Refs. 2 and 3). One of the foremost characterized target genes of p53 is the mdm2 gene. MDM2 protein possesses E3 ubiquitin ligase activity toward p53 that plays a role in the negative regulation of p53 and its degradation by the proteasome (for review, see Ref. 4).Through its ability to ubiquitylate p53 and target it for proteasomal degradation, MDM2 plays a key role in maintaining p53 at very low levels under non-stress conditions. In such circumstances MDM2 and p53 form a negative feedback loop in which p53 induces mdm2 transcription and MDM2 targets p53 for degradation (2). In stress situations, MDM2-dependent degradation of p53 is inhibited by a variety of mechanisms, including p14ARF binding to MDM2, phosphorylation of the C terminus of MDM2 by the ATM kinase, stress-induced phosphorylation of sites in the trans-activation domain of p53, subsequent binding of the p300 coactivator, and further acetylation of p53 in its C-terminal region (5), which results in an increase of the steady-state level of the p53 transcription factor and consequential flux in the expression of more than a hundred genes, including those involved in cell cycle arrest, senescence, and apoptosis (2).Recent reports indicate that apart from its initially discovered RING finger-dependent enzymatic E3 ubiquitin ligase activity, MDM2 has other functions. A hydroph...

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“…Within the range of physiological temperatures of a human body, even the most structured part of a purified WT (wild-type) p53-the DBD (DNA-binding domain)-unfolds, adopts inactive misfolded conformations and aggregates at a relatively high rate (Hansen et al, 1996;Muller et al, 2004;Butler and Loh, 2006). It is not clear whether this feature is directly required for p53's role as an important control node of the cellular reaction to DNA damage and other stress, but this intrinsic p53 instability has been preserved during the evolution (Canadillas et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Hsp70 molecular chaperones are required to support p53 tumor suppressor activity under stress conditions

et al. 2009

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p53 as an unstable protein in vitro likely requires stabilizing factors to act as a tumor suppressor in vivo. Here, we show that in human cells transfected with wildtype (WT) p53, Hsp90 and Hsp70 molecular chaperones maintain the p53 native conformation under heat-shock conditions (42 1C) as well as assist p53 refolding at 37 1C, during the recovery from heat shock. We also show that the interaction of WT p53 with WAF1 promoter in cells is sensitive to Hsp70 and Hsp90 inhibition already at 37 1C and further decreased on heat shock. The influence of chaperones on p53 binding to the WAF1 promoter sequence has been confirmed in vitro, using highly purified proteins. Hsp90 stabilizes the binding of p53 to the promoter sequence at 37 1C, whereas under heat-shock conditions the requirement for the Hsp70-Hsp40 system and its cooperation with Hsp90 increases. Hop co-chaperone additionally stimulates these reactions. Interestingly, the combined Hsp90 and Hsp70-Hsp40 allow for a limited in vitro restoration of the DNA-binding activity by the p53 oncogenic variant R249S and affect its conformation in cells. Our results indicate for the first time that, especially under stress conditions, not only Hsp90 but also Hsp70 is required for the chaperoning of WT and R249S p53.

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Hsp90 Regulates the Activity of Wild Type p53 under Physiological and Elevated Temperatures

Cited by 134 publications

References 68 publications

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

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

MDM2 Chaperones the p53 Tumor Suppressor

Hsp70 molecular chaperones are required to support p53 tumor suppressor activity under stress conditions

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