In Vivo Function of Hsp90 Is Dependent on ATP Binding and ATP Hydrolysis

Obermann, Wolfgang M. J.; Sondermann, Holger; Russo, Alicia A.; Pavletich, Nikola P.; Hartl, F. Ulrich

doi:10.1083/jcb.143.4.901

Cited by 555 publications

(545 citation statements)

References 64 publications

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“…Although Hsp90 is the direct target of GA and its clinically relevant derivatives, inhibition of Hsp90's relatively weak ATPase activity itself is unlikely to be useful as a pharmacodynamic endpoint of drug therapy in patients. 44 Hsp90 activity can be assessed in tumor samples indirectly by evaluating changes in levels of client proteins that are regulated by Hsp90. The functions of numerous cancer-associated proteins are regulated by Hsp90 and are altered by Hsp90 inhibitors, [45][46][47][48] but it is not yet clear which of the affected proteins will be most predictive of activity against a particular tumor type in vivo.…”

Section: Discussionmentioning

confidence: 99%

Hsp90 inhibitors deplete key anti‐apoptotic proteins in pediatric solid tumor cells and demonstrate synergistic anticancer activity with cisplatin

Bagatell

Beliakoff

Marron

et al. 2004

Intl Journal of Cancer

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Section: Discussionmentioning

confidence: 99%

Hsp90 inhibitors deplete key anti‐apoptotic proteins in pediatric solid tumor cells and demonstrate synergistic anticancer activity with cisplatin

Bagatell

Beliakoff

Marron

et al. 2004

Intl Journal of Cancer

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“…The chaperone activity of HSP90 is inhibited by ansamycin antibiotics (GA) [18]. Recently, it has been published that the in i o function of HSP90 is dependent on ATP binding and ATP hydrolysis [21,22]. Furthermore, an important result has been reported that HSP90 acts as a capacitor for morphological evolution [41].…”

Section: Discussionmentioning

confidence: 99%

“…The chaperone activity was suppressed almost completely at a molar ratio of 1 : 10 (HSP90 : CDDP). The CDDP concentration (1n5 µM) is lower than that of the GA concentration (18 µM) which inhibits the ATPase activity of HSP90 almost completely [21]. Next, we investigated the influence of Mg\ATP on this assay system.…”

Section: Figure 5 Effect Of Cddp On the Chaperone Activity Of Hsp90mentioning

confidence: 99%

“…On the contrary, the COOH-terminal fragment binds to partially folded proteins in an ATP-independent manner. Recently, it has been reported that the in i o function of HSP90 is dependent on ATP binding and ATP hydrolysis [21,22]. Thus, HSP90 contains two independent chaperone sites ; both NH # -and COOH-domains suppress protein aggregation, with differential specificity.…”

Section: Introductionmentioning

confidence: 99%

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A novel chaperone-activity-reducing mechanism of the 90-kDa molecular chaperone HSP90

Itoh

Ogura

Komatsuda

et al. 1999

Biochemical Journal

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The 90-kDa heat shock protein (HSP90) acts as a specific molecular chaperone in the folding and regulates a wide range of associated proteins such as steroid hormone receptors. It is known that HSP90 possesses two different chaperone sites, both in the N-and C-domains, and that the chaperone activity of HSP90 is blocked by binding of geldanamycin (GA) to the Ndomain, the same as the ATP-binding site. Here we show that Cisplatin [cis-diamminedichloroplatinum (II), CDDP], an antineoplastic agent, associates with HSP90 and reduces its chaperone activity. In order to analyse the binding proteins, bovine brain cytosols were applied to a CDDP-affinity column and binding proteins were eluted by CDDP. In the elutants, only 90-kDa protein bands were detected on SDS\PAGE, and the protein was cross-reacted with the anti-HSP90 antibody on immunoblotting. No protein bands were detected in the elutants

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“…27,28 These agents disrupt HSP90 association with client proteins by occupying the nucleotide-binding site of HSP90, [29][30][31] therefore, preventing binding of HSP90 with ATP and affecting the composition of HSP90 containing multimolecular chaperone complexes. 32, 33 In view of evidence of activity in preclinical animal models, 34 …”

Section: Discussionmentioning

confidence: 99%

Heat shock protein inhibitors increase the efficacy of measles virotherapy

Liu

Erlichman

et al. 2008

Gene Ther

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Oncolytic measles virus strains have activity against multiple tumor types and are currently in phase I clinical testing. Induction of the heat shock protein 70 (HSP70) constitutes one of the earliest changes in cellular gene expression following infection with RNA viruses including measles virus, and HSP70 upregulation induced by heat shock has been shown to result in increased measles virus cytotoxicity. HSP90 inhibitors such as geldanamycin (GA) or 17-allylaminogeldanamycin result in pharmacologic upregulation of HSP70 and they are currently in clinical testing as cancer therapeutics. We therefore investigated the hypothesis that heat shock protein inhibitors could augment the measles virus-induced cytopathic effect. We tested the combination of a measles virus derivative expressing soluble human carcinoembryonic antigen (MV-CEA) and GA in MDA-MB-231 (breast), SKOV3.IP (ovarian) and TE671 (rhabdomyosarcoma) cancer cell lines. Optimal synergy was accomplished when GA treatment was initiated 6-24 h following MV infection. Western immunoblotting confirmed HSP70 upregulation in combination-treated cells. Combination treatment resulted in statistically significant increase in syncytia formation as compared to MV-CEA infection alone. Clonogenic assays demonstrated significant decrease in tumor colony formation in MV-CEA/GA combination-treated cells. In addition there was increase in apoptosis by 4,6-diamidino-2-phenylindole staining. Western immunoblotting for caspase-9, caspase-8, caspase-3 and poly(ADP-ribose) polymerase (PARP) demonstrated increase in cleaved caspase-8 and PARP. The pan-caspase inhibitor Z-VAD-FMK and caspase-8 inhibitor Z-IETD-FMK, but not the caspase-9 inhibitor Z-IEHD-FMK, protected tumor cells from MV-CEA/GA-induced PARP activation, indicating that apoptosis in combinationtreated cells occurs mainly via the extrinsic caspase pathway. Treatment of normal cells, such as normal human fibroblasts, however, with the MV-CEA/GA combination, did not result in cytopathic effect, indicating that GA did not alter the MV-CEA specificity for tumor cells. One-step viral growth curves, western immunoblotting for MV-N protein expression, QRT-PCR quantitation of MV-genome copy number and CEA levels showed comparable proliferation of MV-CEA in GAtreated vs -untreated tumor cells. Rho activation assays and western blot for total RhoA, a GTPase associated with the actin cytoskeleton, demonstrated decrease in RhoA activation in combination-treated cells, a change previously shown to be associated with increase in paramyxovirus-induced cell-cell fusion. The enhanced cytopathic effect resulting from measles virus/GA combination supports the translational potential of this approach in the treatment of cancer.

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In Vivo Function of Hsp90 Is Dependent on ATP Binding and ATP Hydrolysis

Cited by 555 publications

References 64 publications

Hsp90 inhibitors deplete key anti‐apoptotic proteins in pediatric solid tumor cells and demonstrate synergistic anticancer activity with cisplatin

Hsp90 inhibitors deplete key anti‐apoptotic proteins in pediatric solid tumor cells and demonstrate synergistic anticancer activity with cisplatin

A novel chaperone-activity-reducing mechanism of the 90-kDa molecular chaperone HSP90

Heat shock protein inhibitors increase the efficacy of measles virotherapy

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