Differential In Vivo Regulation of Steroid Hormone Receptor Activation by Cdc37p

Fliss, Albert; Fang, Yifang; Boschelli, Frank; Caplan, Avrom J.

doi:10.1091/mbc.8.12.2501

Cited by 51 publications

(54 citation statements)

References 45 publications

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“…Optimal AR activation requires the input of a number of protein kinases, and decreased AR activity after Cdc37 depletion may involve targeting such kinases. However, given previous publications suggesting direct interaction of Cdc37 with AR, it is likely that inhibition of AR-dependent transcription involves both Cdc37 binding to AR and the indirect effects of the protein kinase targeting mentioned above (13,37). Because the bulk of early prostate cancers are androgen responsive, Cdc37 inhibition could be an effective therapy for this subgroup and might be developed into a therapy aimed at preventing the conversion of early-stage tumors into more difficult to treat metastatic androgen-independent types.…”

Section: Discussionmentioning

confidence: 99%

Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells

Gray

Stevenson²,

Calderwood³

2007

Cancer Research

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Members of the 90-kDa heat shock protein (HSP90) family are known to bind and stabilize intermediates in a wide variety of cell signaling pathways and contribute to their dysregulation in cancer. An important intracellular cofactor for HSP90 is Cdc37, a protein with a broad role in fostering the activities of protein kinases. By targeting Cdc37 using RNA interference, we have shown that the loss of Cdc37 function induces irreversible growth arrest in androgen receptor-positive and -negative prostate carcinoma cells. In contrast to HSP90-directed agents, Cdc37 targeting seems to affect cancer cells through a distinct mechanism and does not significantly deplete the intracellular levels of most known HSP90 client proteins. Instead, Cdc37 depletion inhibits cellular kinase activity and flux through growth-promoting signal transduction cascades. We show that the loss of Cdc37 leads to reduced activity of the Erk, Akt, mTOR, and androgen-induced pathways. We have also discovered synergistic interactions between Cdc37 inactivation and the HSP90-inhibitory anticancer drug 17-(allylamino)-17-demethoxygeldanamycin (17AAG). These interactions involve enhanced degradation of proteins essential for growth and inhibition of 17AAG-induced expression of the antiapoptotic HSP70. Thus, Cdc37 is essential for maintaining prostate tumor cell growth and may represent a novel target in the search for multitargeted therapies based on the HSP90 chaperone system. [Cancer Res 2007;67(24):11942-50]

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Section: Discussionmentioning

confidence: 99%

Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells

Gray

Stevenson²,

Calderwood³

2007

Cancer Research

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“…Rabbit reticulocyte lysates (treated) were obtained from Promega. Antisera to Hsp90, Cdc37, and the AR were described previously (18,19). Nitrocellulose membranes were from Immobilon and polyvinylidene difluoride membranes were from Millipore.…”

Section: Methodsmentioning

confidence: 99%

“…18). The cells were grown in glucose or galactose containing selective medium to A 600 ϭ 0.2, and 1-ml aliquots were incubated with 100 nM 3 H-R1881 (diluted 1:5 with unlabeled R1881 of the same concentration), plus or minus 100-fold excess of cold R1881.…”

Section: Methodsmentioning

confidence: 99%

“…Cdc37 is required for the folding of several protein kinases and was proposed to be kinase specific based on its failure to interact with aryl hydrocarbon receptor, estrogen receptor, GR, or PR in vitro (15)(16)(17). On the other hand, genetic studies using the yeast Saccharomyces cerevisiae as a model system showed that Cdc37 was important for hormone-dependent activity by AR but not by GR (18). These studies also revealed that Cdc37 functions at a later stage in the folding process compared with Hsp90 or Ydj1p.…”

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Functional Interaction of Human Cdc37 with the Androgen Receptor but Not with the Glucocorticoid Receptor

Rao

Lee

Benzeno

et al. 2001

Journal of Biological Chemistry

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Cdc37 is a molecular chaperone closely associated with the folding of protein kinases. Results from studies using a yeast model system showed that it was also important for activation of the human androgen receptor (AR). Based on results from the yeast model system (Fliss, A. E., Fang, Y., Boschelli, F., and Caplan, A. J. (1997) Mol. Biol. Cell 8, 2501-2509), we initiated studies to address whether AR and Cdc37 interact with each other in animal cell systems. Our results show that Cdc37 binds to AR but not to glucocorticoid receptors (GR) synthesized in rabbit reticulocyte lysates. This binding occurs via the ligand-binding domain of the AR in a manner that is partially dependent on Hsp90 and the presence of hormone. Further studies using the yeast system showed that Cdc37 is not interchangeable with Hsp90, suggesting that it functions at a distinct step in the activation pathway. Expression of a dominant negative form of Cdc37 in animal cells down-regulates full-length AR but has very little effect on an AR truncation lacking the ligand-binding domain or fulllength GR. These results reveal differences in the mechanisms by which AR and GR become active transcription factors and strengthen the notion that Cdc37 has a wider range of polypeptide clients than was realized previously.

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“…Folding of protein kinases, for example, requires a cochaperone called Cdc37, that does not associate with GR or PR, although it does function in activation of androgen receptor and a viral reverse transcriptase (Fliss et al, 1997;Rao et al, 2001;Wang et al, 2002). Cdc37 interacts with many different protein kinases and is an essential gene (Hunter and Poon, 1997).…”

Section: Introductionmentioning

confidence: 99%

Sti1 and Cdc37 Can Stabilize Hsp90 in Chaperone Complexes with a Protein Kinase

Lee

Shabbir

Cardozo

et al. 2004

MBoC

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Hsp90 functions in association with several cochaperones for folding of protein kinases and transcription factors, although the relative contribution of each to the overall reaction is unknown. We assayed the role of nine different cochaperones in the activation of Ste11, a Saccharomyces cerevisiae mitogen-activated protein kinase kinase kinase. Studies on signaling via this protein kinase pathway was measured by ␣-factor-stimulated induction of FIG1 or lacZ, and repression of HHF1. Several cochaperone mutants tested had reduced FIG1 induction or HHF1 repression, although to differing extents. The greatest defects were in cpr7⌬, sse1⌬, and ydj1⌬ mutants. Assays of Ste11 kinase activity revealed a pattern of defects in the cochaperone mutant strains that were similar to the gene expression studies. Overexpression of CDC37, a chaperone required for protein kinase folding, suppressed defects the sti1⌬ mutant back to wild-type levels. CDC37 overexpression also restored stable Hsp90 binding to the Ste11 protein kinase domain in the sti1⌬ mutant strain. These data suggest that Cdc37 and Sti1 have functional overlap in stabilizing Hsp90:client complexes. Finally, we show that Cns1 functions in MAP kinase signaling in association with Cpr7. INTRODUCTIONAmong several major classes of molecular chaperone that have been characterized, Hsp90 appears to function primarily in folding of signal transducing proteins such as transcription factors and protein kinases (Caplan, 1999;Prodromou and Pearl, 2003). Hsp90 does not act alone in this capacity, but in association with several cochaperones that may also have chaperone function as defined by their ability to prevent polypeptide aggregation in vitro.The current understanding of how Hsp90 cochaperones function derived from in vitro studies on progesterone receptors (PR) and glucocorticoid receptors (GR; Toft, 1997, 2003). The results of these studies showed that Hsp70 and Hsp40 first interact with the receptor ligandbinding domain. Hsp90 is recruited into this complex by the cochaperone called Hop, which interacts with both Hsp90 and Hsp70. Subsequently, Hsp70 and Hop are displaced by other cochaperones, such as one of many immunophilins and p23. Folding occurs in association with ATP hydrolysis by Hsp90, which is stimulated by another cochaperone called Aha1 (and its paralog Hch1; Panaretou et al., 2002;Lotz et al., 2003). It is unclear whether folding occurs while the receptor is in association with Hsp90 or after its release. Whether the cochaperones are required for this reaction is not clear, because purified Hsp70 and Hsp90 can together facilitate folding of GR in vitro, whereas cochaperones such as Hop stimulate the reaction (Morishima et al., 2000;Rajapandi et al., 2000). Furthermore, deletion of yeast Hop (STI1), or p23 (SBA1) does not result in a slow growth phenotype except under stress conditions (Nicolet and Craig, 1989;Chang et al., 1997;Bohen, 1998;Fang et al., 1998).Another question is whether the scheme described above for nuclear receptors reflects a set of ...

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Differential In Vivo Regulation of Steroid Hormone Receptor Activation by Cdc37p

Cited by 51 publications

References 45 publications

Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells

Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells

Functional Interaction of Human Cdc37 with the Androgen Receptor but Not with the Glucocorticoid Receptor

Sti1 and Cdc37 Can Stabilize Hsp90 in Chaperone Complexes with a Protein Kinase

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