Hsp90 Regulates Androgen Receptor Hormone Binding Affinity in Vivo

Fang, Yifang; Fliss, Albert; Robins, Diane M.; Caplan, Avrom J.

doi:10.1074/jbc.271.45.28697

Cited by 207 publications

(176 citation statements)

References 34 publications

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“…Previous studies had demonstrated that it is possible to selectively abolish specific dispensable functions of Hsp90 without compromising its ability to ensure viability in yeast; specifically, a variety of HSP82 mutations result in a defect in the regulation of steroid receptors or v-Src or folding of p53 in yeast (Picard et al, 1990;Bohen and Yamamoto, 1993;Xu and Lindquist, 1993;Bohen, 1995;Nathan and Lindquist, 1995;Blagosklonny et al, 1996;Fang et al, 1996;Nathan et al, 1997). We have now considerably extended this theme by showing that even subtle point mutations can discriminate between the Hsp90 requirements in two different signaling pathways.…”

Section: Genetic Dissection Of Different Hsp90 Functionsmentioning

confidence: 73%

“…Further insights into the role of Hsp90 in the regulation of this particular signal transduction pathway come from studies made in yeast (reviewed in Picard, 1998). Vertebrate steroid receptors expressed in yeast strains with a low level (Picard et al, 1990; see also Holley and Yamamoto, 1995) or specific point mutants of Hsp82 (Bohen and Yamamoto, 1993;Bohen, 1995;Nathan and Lindquist, 1995;Fang et al, 1996) show a defective hormonal response that is due to a decrease in the ligand-binding affinity (Bohen, 1995;Fang et al, 1996). Thus, Hsp90 may have a dual role: it ensures that receptors are kept inactive in the absence of hormone and helps them to respond specifically and efficiently to ligand.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hsp90 Is Required for Pheromone Signaling in Yeast

Louvion

Abbas-Terki

Picard

1998

MBoC

107

129

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The heat-shock protein 90 (Hsp90) is a cytosolic molecular chaperone that is highly abundant even at normal temperature. Specific functions for Hsp90 have been proposed based on the characterization of its interactions with certain transcription factors and kinases including Raf in vertebrates and flies. We therefore decided to address the role of Hsp90 for MAP kinase pathways in the budding yeast, an organism amenable to both genetic and biochemical analyses. We found that both basal and induced activities of the pheromone-signaling pathway depend on Hsp90. Signaling is defective in strains expressing low levels or point mutants of yeast Hsp90 (Hsp82), or human Hsp90␤ instead of the wild-type protein. Ste11, a yeast equivalent of Raf, forms complexes with wild-type Hsp90 and depends on Hsp90 function for accumulation. For budding yeast, Ste11 represents the first identified endogenous "substrate" of Hsp90. Moreover, Hsp90 functions in steroid receptor and pheromone signaling can be genetically separated as the Hsp82 point mutant T525I and the human Hsp90␤ are specifically defective for the former and the latter, respectively. These findings further corroborate the view that molecular chaperones must also be considered as transient or stable components of signal transduction pathways. INTRODUCTIONThe 90-kDa heat-shock protein (Hsp90) 1 (for reviews, see Jakob and Buchner, 1994;Csermely et al., 1998) is an ubiquitous and abundantly expressed cytosolic protein even at normal temperature. It is highly conserved from bacteria to mammals. Two genes encode closely related isoforms in mammals as well as in the budding yeast Saccharomyces cerevisiae. Deletion experiments in yeast have shown that the expression of at least one of the two Hsp90 isoforms, either Hsp82 or Hsc82, is essential for viability (Borkovich et al., 1989). Similarly, many mutant alleles of the Drosophila HSP90 homolog, HSP83, are embryonic lethals over a deficiency of the locus (van der Straten et al., 1997), whereas the Escherichia coli homolog of Hsp90, HtpG, appears to be dispensable (Bardwell and Craig, 1988). Hsp90 can act as a molecular chaperone in vitro to promote refolding of denatured proteins (Wiech et al., 1992;Yonehara et al., 1996; see also Shaknovich et al., 1992;Shue and Kohtz, 1994), to hold denatured proteins in a folding-competent state for other chaperones (Freeman and Morimoto, 1996;Yonehara et al., 1996) and to prevent protein unfolding and aggregation (Miyata and Yahara, 1992;Jakob et al., 1995aJakob et al., , 1995bYonehara et al., 1996).The interaction of Hsp90 with steroid receptors, which can be thought of as a signal transduction complex, has been the most extensively investigated. A variety of in vitro and in vivo studies have revealed that steroid receptors are complexed with Hsp90 and several other proteins in the absence of hormone (for review, see Pratt and Toft, 1997). Upon ligand binding, the hormone binding domain (HBD) undergoes a conformational change that results in the release of Hsp90 and the concomitant acti...

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Section: Genetic Dissection Of Different Hsp90 Functionsmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Hsp90 Is Required for Pheromone Signaling in Yeast

Louvion

Abbas-Terki

Picard

1998

MBoC

107

129

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“…A requirement for Hsp90 in androgen binding to AR was reported previously (27). Geldanamycin, an inhibitor of the Hsp90 chaperone function (58), inhibits androgen binding, increases AR degradation, and inhibits AR functional activity (27,59).…”

Section: Discussionmentioning

confidence: 99%

“…One possible interaction site is the AR ligand-binding domain, which was shown to bind the Hsp70⅐Hsp90 heterocomplex (27,28), and Hsp70⅐Hsp90 interacts with CHIP (23). A recent study demonstrating that CHIP functions as a dimer provides a basis for this type of interaction (29).…”

Section: Fig 3 Interaction Of Chip With the Ar Nh 2 -Terminal Consementioning

confidence: 99%

An Androgen Receptor NH2-terminal Conserved Motif Interacts with the COOH Terminus of the Hsp70-interacting Protein (CHIP)

He¹,

Bai²,

Hnat³

et al. 2004

Journal of Biological Chemistry

122

113

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The NH 2 -terminal sequence of steroid receptors is highly variable between different receptors and in the same receptor from different species. In this study, a primary sequence homology comparison identified a 14-amino acid NH 2 -terminal motif of the human androgen receptor (AR) that is common to AR from all species reported, including the lower vertebrates. The evolutionarily conserved motif is unique to AR, with the exception of a partial sequence in the glucocorticoid receptor of higher species. The presence of the conserved motif in AR and the glucocorticoid receptor and its absence in other steroid receptors suggests convergent evolution. The function of the AR NH 2 -terminal conserved motif was suggested from a yeast two-hybrid screen that identified the COOH terminus of the Hsp70-interacting protein (CHIP) as a binding partner. We found that CHIP functions as a negative regulator of AR transcriptional activity by promoting AR degradation. In support of this, two mutations in the AR NH 2 -terminal conserved motif previously identified in the transgenic adenocarcinoma of mouse prostate model reduced the interaction between CHIP and AR. Our results suggest that the AR NH 2 -terminal domain contains an evolutionarily conserved motif that functions to limit AR transcriptional activity. Moreover, we demonstrate that the combination of comparative sequence alignment and yeast two-hybrid screening using short conserved peptides as bait provides an effective strategy to probe the structure-function relationships of steroid receptor NH 2 -terminal domains and other intrinsically unstructured transcriptional regulatory proteins.Steroid receptors depend on multiple domains for their function as ligand-dependent transcriptional activators. The DNAand ligand-binding domains have been studied extensively and have a high degree of structural and functional conservation. In contrast, the largely unstructured NH 2 -terminal domains (1-3) are highly variable in size and sequence, and the molecular mechanisms that contribute to transactivation are not well understood. The size of the NH 2 -terminal region of steroid receptors increases with evolutionary expansion (4, 5), from estrogen receptor-␣ (185 amino acid residues) to the glucocorticoid receptor (GR 1 ; 420 residues), androgen receptor (AR; 558 residues), progesterone receptor (B form; 566 residues), and mineralocorticoid receptor (602 residues). In contrast, transcription factors such as p53, NF-B, and VP16 typically have transcriptional activation domains of Ͻ100 residues.

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“…In the absence of a ligand, the AR is associated with Hsp90 in the cytoplasm and kept in a high-affinity hormonebinding conformation necessary for ligand binding. As a consequence, inhibition of the chaperone function of Hsp90 impairs the AR ligand-binding ability (Fang et al, 1996;Georget et al, 2002) With the aim of elucidating the mechanism behind the genotoxic stressinduced loss of AR activity, the ligand-binding ability of the AR in the presence of etoposide and cisplatin was investigated. Hormone-deprived LNCaP cells were stimulated with radiolabeled DHT for 1 h in the presence or absence of etoposide and cisplatin.…”

Section: Genotoxic Stress-induced Inhibition Of Ar Activitymentioning

confidence: 99%

Androgen receptor activity is inhibited in response to genotoxic agents in a p53-independent manner

2006

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The androgen receptor (AR) is fundamental to androgen signalling within the prostate gland, and deregulation of its activity is frequently linked to the development of prostate cancer. Advanced prostate cancer is often treated with chemotherapy and most of these drugs exert their function by generating genotoxic stress such as DNA damage. We have investigated here the effects of genotoxic agents used in chemotherapeutic regimens on AR function and expression. We have discovered that endogenous AR activity in LNCaP cells is inhibited in response to the chemotherapeutic agents etoposide and cisplatin. This loss of AR activity is not caused by a change in cell cycle distribution, a change in subcellular localisation of the AR nor by induction of apoptosis. In addition, we found that inhibition of AR activity in response to genotoxic stress is independent of p53 function. Interestingly, our studies revealed that genotoxic stress inhibits the hormone-stimulated recruitment of AR to androgen response elements. Thus, we report for the first time a mechanism by which the AR activity is inhibited in response to different chemotherapeutic agents.

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Hsp90 Regulates Androgen Receptor Hormone Binding Affinity in Vivo

Cited by 207 publications

References 34 publications

Hsp90 Is Required for Pheromone Signaling in Yeast

Hsp90 Is Required for Pheromone Signaling in Yeast

An Androgen Receptor NH2-terminal Conserved Motif Interacts with the COOH Terminus of the Hsp70-interacting Protein (CHIP)

Androgen receptor activity is inhibited in response to genotoxic agents in a p53-independent manner

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