Molecular Mechanism of Inhibition of the Human Protein Complex Hsp90–Cdc37, a Kinome Chaperone–Cochaperone, by Triterpene Celastrol

Sreeramulu, Sridhar; Gande, S.L.; Göbel, Michael; Schwalbe, Harald

doi:10.1002/anie.200900929

Cited by 158 publications

(158 citation statements)

References 15 publications

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“…We thought that celastrol might attack an import region in HSP90 thus exert broad effects. To support this, celastrol has been reported to interact directly with the C-terminal of HSP90 ), and we have also got preliminary evidence that celastrol can directly attack the thiols on HSP90's C-terminal (data not shown), in addition to the already reported Cdc37 thiols (Sreeramulu et al 2009). …”

Section: Discussionsupporting

confidence: 73%

“…Analysis of gene expression patterns provided further support to this line of thought (Hieronymus et al 2006), and corroborating data rapidly accumulated (Sreeramulu et al 2009;Zhang et al 2008). Since HSP90 inhibition clearly explained nearly all of celastrol's reported actions [including inhibition of NF-κB (He et al 2009a;Zhang et al 2006), antitumor effects in various cell lines (Nagase et al 2003;Sethi et al 2007;Yang et al 2006), and neuron degenerative disease amelioration (Chow and Brown 2007;Faust et al 2009, Kiaei et al 2005], the molecular basis for celastrol's HSP90 inhibition was intensively explored (Sreeramulu et al 2009;Trott et al 2008;Zhang et al 2008Zhang et al , 2009). Celastrol's main target(s) in the HSP90 complex, however, remain debatable.…”

Section: Introductionmentioning

confidence: 73%

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Celastrol regulates multiple nuclear transcription factors belonging to HSP90's clients in a dose- and cell type-dependent way

Zhang

Cao

et al. 2010

Cell Stress and Chaperones

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Celastrol, a novel HSP90 inhibitor, has recently attracted much attention due to its potential in multiple applications, such as anti-inflammation use, degenerative neuron disease relief, and tumor management. At present, the studies in celastrol's effects on HSP90's clients have focused on the kinase sub-population, while another key sub-population, nuclear transcription factors (TFs), is not being well-explored. In this study, we observe the effects of celastrol on 18 TFs (belonging to HSP90 clients) in three human cell lines: MCF-7 (breast cancer), HepG2 (hepatoma), and THP-1 (monocytic leukemia). The results show that at least half of the detectable TFs were affected by celastrol, though the effect patterns varied with cell type and dosage. Bi-directional regulations of some TFs were identified, a phenomenon not yet seen with other HSP90 inhibitors. Celastrol's capability to affect multiple TFs was consistent with its altering HSP90/TFs interactions and disrupting HSP90/Hop interaction, in addition to the reported damaging HSP90/Cdc37 interaction. This work confirms, for the first time, that celastrol has broad effects on TFs belonging to HSP90's clients, casts new light on understanding these reported actions, and suggests new possible applications for celastrol, such as diabetes management.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 73%

Celastrol regulates multiple nuclear transcription factors belonging to HSP90's clients in a dose- and cell type-dependent way

Zhang

Cao

et al. 2010

Cell Stress and Chaperones

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“…Celastrol thus promotes the destruction of NF-B, a factor that contributes to cancer development [6]. Second, celastrol prevents the interaction between HSP90 and Cdc37 through binding to three CYS residues on HSP90 [7]. This complex activates numerous protein kinases that are described as oncogenic [8].…”

Section: Examples Of Qms That Are Anticancer Compoundsmentioning

confidence: 99%

“…14) [99]. These species, although not closely related to standard QMs, as they undergo a [1][2][3][4][5][6][7][8] addition, can be generated in situ by irradiation between 310 and 360 nm. The QMs originating from binaphtols were 100-fold more reactive that the naphthyl QMs, and they were also produced from the water-soluble leaving group, trimethylammonium iodide; the QMs obtained were also able to alkylate DNA.…”

Section: Drugs That Release Qms That React Preferentially With Proteimentioning

confidence: 99%

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Dufrasne¹,

Gelbcke²,

Nève³

et al. 2011

CMC

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Abstract:The importance of reactive drug metabolites in the pathogenesis of drug-induced toxicity has been investigated since the early 1950s, mainly to reveal the link between toxic metabolites and chemical carcinogenesis. This review mainly focuses on biologically active compounds, which generate reactive quinone methide (QM) intermediates either directly or after bioactivation. Several examples of anticancer drugs acting through the generation of QM electrophiles are given. The use of those drugs for chemotherapeutic purposes is also discussed. The key feature of those QM-generating drugs is their reactivity toward specific nucleophilic biological targets. Modulation of their reactivity represents a challenge for medicinal chemists because, depending on the reactivity of these QM intermediates, their interaction with critical proteins can alter the function of these key proteins and induce a wide variety of responses with functional consequences. Among the possible consequences, antiproliferative effects could be exploited for chemotherapeutic purposes. Information on how such QM-generating drugs can affect individual target proteins and their functional consequences are required to help the medicinal chemist in the design of more specific QM-generating molecules for chemotherapeutic use.

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“…However, whether this interaction is involved in the control of LKB1 protein stability was not determined. To address this question, we first used the triterpene celastrol, a specific Cdc37 inhibitor that interferes with Hsp90-Cdc37 chaperoning function (Hieronymus et al, 2006;Sreeramulu et al, 2009;Zhang et al, 2009). We sought to determine the effects of celastrol on exogenous and endogenous LKB1.…”

Section: Lkb1 Stability Is Regulated By the Molecular Chaperone Cdc37mentioning

confidence: 99%

Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1

et al. 2011

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LKB1 is a tumor suppressor that is constitutionally mutated in a cancer-prone condition, called Peutz-Jeghers syndrome, as well as somatically inactivated in a sizeable fraction of lung and cervical neoplasms. The LKB1 gene encodes a serine/threonine kinase that associates with the pseudokinase STRAD (STE-20-related pseudokinase) and the scaffolding protein MO25, the formation of this heterotrimeric complex promotes allosteric activation of LKB1. We have previously reported that the molecular chaperone heat shock protein 90 (Hsp90) binds to and stabilizes LKB1. Combining pharmacological studies and RNA interference approaches, we now provide evidence that the co-chaperone Cdc37 participates to the regulation of LKB1 stability. It is known that the Hsp90-Cdc37 complex recognizes a surface within the N-terminal catalytic lobe of client protein kinases. In agreement with this finding, we found that the chaperones Hsp90 and Cdc37 interact with an LKB1 isoform that differs in the C-terminal region, but not with a novel LKB1 variant that lacks a portion of the kinase N-terminal lobe domain. Reconstitution of the two complexes LKB1-STRAD and LKB1-Hsp90-Cdc37 with recombinant proteins revealed that the former is catalytically active whereas the latter is inactive. Furthermore, consistent with a documented repressor function of Hsp90, LKB1 kinase activity was transiently stimulated upon dissociation of Hsp90. Finally, disruption of the LKB1-Hsp90 complex favors the recruitment of both Hsp/Hsc70 and the U-box dependent E3 ubiquitin ligase CHIP (carboxyl terminus of Hsc70-interacting protein) that triggers LKB1 degradation. Taken together, our results establish that the Hsp90-Cdc37 complex controls both the stability and activity of the LKB1 kinase. This study further shows that two chaperone complexes with antagonizing activities, Hsp90-Cdc37 and Hsp/Hsc70-CHIP, finely control the cellular level of LKB1 protein.

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Molecular Mechanism of Inhibition of the Human Protein Complex Hsp90–Cdc37, a Kinome Chaperone–Cochaperone, by Triterpene Celastrol

Cited by 158 publications

References 15 publications

Celastrol regulates multiple nuclear transcription factors belonging to HSP90's clients in a dose- and cell type-dependent way

Celastrol regulates multiple nuclear transcription factors belonging to HSP90's clients in a dose- and cell type-dependent way

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1

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