Members of the 70-kilodalton heat shock protein family contain a highly conserved calmodulin-binding domain.

Stevenson, Mary Ann; Calderwood, Stuart K.

doi:10.1128/mcb.10.3.1234

Cited by 97 publications

(54 citation statements)

References 25 publications

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“…Horseradish peroxidase (HRP)-conjugated secondary antibodies were purchased from Invitrogen. Pan-HSP70 antibody was created in-house as previously described (24).…”

Section: Methodsmentioning

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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“…Horseradish peroxidase (HRP)-conjugated secondary antibodies were purchased from Invitrogen. Pan-HSP70 antibody was created in-house as previously described (24).…”

Section: Methodsmentioning

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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“…Interestingly, Ca 2+ ions which inhibit the ATPase, stimulate the autophosphorylation activity, indicating a regulatory role of Ca 2+ (CEGIELSKA and GEORGOPOULOS 1989). The existence of a highly conserved calmodulin-like binding domain in various members of the hsp70 family may be of relevance in this context (STEVENSON and CALDERWOOD 1990).…”

Section: Dnak-the Prokaryotic Homologuementioning

confidence: 99%

Heat Shock Proteins hsp60 and hsp70: Their Roles in Folding, Assembly and Membrane Translocation of Proteins

Langer¹,

Neupert²

1991

Current Topics in Microbiology and Immunology

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“…Previous reports have shown that members of the Hsp70 family bind CaM in a calcium-dependent manner (Stevenson and Calderwood 1990). Heat shock could increase intracellular Ca 2+ levels and promote the association CaM and Hsp70 (Rocak and Linder 2004;Drummond et al 1986).…”

Section: Discussionmentioning

confidence: 99%

The association of CaM and Hsp70 regulates S-phase arrest and apoptosis in a spatially and temporally dependent manner in human cells

Huang

Wei

Peng

et al. 2009

Cell Stress and Chaperones

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The cell cycle is controlled by regulators functioning at the right time and at the right place. We have found that calmodulin (CaM) has specific distribution patterns during different cell-cycle stages. Here, we identify cell-cycle-specific binding proteins of CaM and examine their function during cell-cycle progression. We first applied immunoprecipitation methods to isolate CaMbinding proteins from cell lysates obtained at different cell-cycle phases and then identified these proteins using mass spectrometry methods. A total of 41 proteins were identified including zinc finger proteins, ribosomal proteins, and heat shock proteins operating in a Ca 2+ -dependent or independent manner. Fifteen proteins were shown to interact with CaM in a cell-phase-specific manner. The association of the selected proteins and CaM were confirmed with in vitro immunoprecipitation and immunostaining methods. One of the identified proteins, heat shock protein 70 (Hsp70), was further studied with respect to its cell-cycle-related function. In vivo fluorescence resonance energy transfer (FRET) analysis showed that the interaction of CaM and Hsp70 was found in the nucleus during the S phase. Overexpression of Hsp70 is shown to arrest cells at S phase and, thus, induce cell apoptosis. When we disrupted the CaM-Hsp70 association with HSP70 truncation without the CaM-binding domain, we found that S-phase arrest and apoptosis could be rescued. The results suggest that the spatial and temporal association of CaM and Hsp70 can regulate cell-cycle progression and cell apoptosis.

show abstract

Members of the 70-kilodalton heat shock protein family contain a highly conserved calmodulin-binding domain.

Cited by 97 publications

References 25 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

Heat Shock Proteins hsp60 and hsp70: Their Roles in Folding, Assembly and Membrane Translocation of Proteins

The association of CaM and Hsp70 regulates S-phase arrest and apoptosis in a spatially and temporally dependent manner in human cells

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