The HSP70 family and cancer

Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia PA 19104.
Carcinogenesis (Impact Factor: 5.33). 04/2013; 34(6). DOI: 10.1093/carcin/bgt111
Source: PubMed


The HSP70 family of heat shock proteins consists of molecular chaperones of approximately 70 kDa in size that serve critical roles in protein homeostasis. These ATPases unfold misfolded or denatured proteins, and can keep these proteins in an unfolded, folding-competent state. They also protect nascently-translating proteins, promote the cellular or organellar transport of proteins, reduce proteotoxic protein aggregates, and serve general housekeeping roles in maintaining protein homeostasis. The HSP70 family is the most conserved in evolution, and all eukaryotes contain multiple members. Some members of this family serve specific organellar- or tissue-specific functions; however, in many cases these members can function redundantly. Overall, the HSP70 family of proteins can be thought of as a potent buffering system for cellular stress, either from extrinsic (physiological, viral, environmental) or intrinsic (replicative or oncogenic) stimuli. As such, this family serves a critical survival function in the cell. Not surprisingly cancer cells rely heavily on this buffering system for survival. The overwhelming majority of human tumors overexpress HSP70 family members, and expression of these proteins is typically a marker for poor prognosis. With the proof of principle that inhibitors of the HSP90 chaperone have emerged as important anti-cancer agents, intense focus has now been placed on the potential for HSP70 inhibitors to assume a role as a significant chemotherapeutic avenue. In this review, the history, regulation, mechanism of action, and role in cancer of the HSP70 family is reviewed. Additionally, the promise of pharmacologically-targeting this protein for cancer therapy is addressed.

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    • "Heat shock proteins (Hsp) are a group of highly conserved proteins involved in the transport and protection of intracellular molecules in stress conditions. Heat shock protein 70 (Hsp70), a prominent member of the Hsp family and the major molecular chaperone, is found in both the cytoplasmic and nuclear compartments of cells, where it participates in folding and translocation of proteins (Murphy, 2013). Similarly to Notch, Hsp70 is expressed in immune cells and has been implicated in several immune processes, including antigen presentation (Srivastava et al., 2012). "
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    ABSTRACT: Notch receptors (Notch1-4) are involved in the differentiation of CD4 T cells and the development of autoimmunity. Mechanisms regulating Notch signaling in CD4 T cells are not fully elucidated. In this study we investigated potential crosstalk between Notch pathway molecules and heat shock protein 70 (Hsp70), the major intracellular chaperone involved in the protein transport during immune responses and other stress conditions. Using Hsp70(-/-) mice we found that Hsp70 is critical for up-regulation of NICD1 and induction of Notch target genes in Jagged1- and Delta-like1-stimulated CD4 T cells. Co-immunoprecipitation analysis of wild-type CD4 T cells stimulated with either Jagged1 or Delta-like1 showed a direct interaction between NICD1 and Hsp70. Both molecules co-localized within the nucleus of CD4 T cells stimulated with Notch ligands. Molecular interaction and nuclear colocalization of NICD1 and Hsp70 were also detected in CD4 T cells reactive against myelin oligodendrocyte glycoprotein (MOG)35-55, which showed Hsp70-dependent up-regulation of both NICD1 and Notch target genes. In conclusion, we demonstrate for the first time that Hsp70 interacts with NICD1 and contributes to the activity of Notch signaling in CD4 T cells. Interaction between Hsp70 and NICD1 may represent a novel mechanism regulating Notch signaling in activated CD4 T cells.
    Journal of neuroimmunology 10/2015; 287:19-26. DOI:10.1016/j.jneuroim.2015.08.007 · 2.47 Impact Factor
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    • "Although the role of APA in modulating Hsp70.3 expression has not been as well explored, HuR has been previously suggested to regulate Hsp70 levels in renal I/R injury [14]. Interestingly , the development of many human tumors is also associated with HuR activation and overexpression of Hsp70 [20] [21] [22]. "
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    ABSTRACT: Heat shock protein 70.3 (Hsp70.3) expression increases in response to cellular stress and plays a cytoprotective role. We have previously shown that Hsp70.3 expression is controlled through coordinated post-transcriptional regulation by miRNAs and alternative polyadenylation (APA), and APA-mediated shortening of the Hsp70.3 3'-UTR facilitates increased protein expression. A stress-induced increase in Hsp70.3 mRNA and protein expression is accompanied by alternative polyadenylation (APA)-mediated truncation of the 3'UTR of the Hsp70.3 mRNA transcript. However, the role that APA plays in stress-induced expression of Hsp70.3 remains unclear. Our results show that APA-mediated truncation of the Hsp70.3 3'UTR increases protein expression through enhanced polyribosome loading. Additionally, we demonstrate that the RNA binding protein HuR, which has been previously shown to play a role in mediating APA, is necessary for heat shock mediated increase in Hsp70.3 mRNA and protein. However, it is somewhat surprising to note that HuR does not play a role in APA of the Hsp70.3 mRNA, and these two regulatory events appear to be mutually exclusive regulators of Hsp70.3 expression. These results not only provide important insight to the regulation of stress response genes following heat shock, but also contribute an enhanced understanding of how alternative polyadenylation contributes to gene regulation. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 02/2015; 1849(6). DOI:10.1016/j.bbagrm.2015.02.004 · 6.33 Impact Factor
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    • "A phenomenon potentially governed by differences in the mechanisms of tumor cell death induced by fractionated versus single dose radiation therapy. Notably in p53 mutated and wildtype glioblastoma cell lines fractionated radiotherapy was reported to promote the release of HSP70 [119], which has been shown to signal DC activation [120]. Interestingly, gene expression profiling of in vitro irradiated breast, prostate and glioma tumor cells also revealed that genes regulating immune (e.g. "
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    ABSTRACT: Over the last decade there has been a dramatic shift in the focus of cancer research towards understanding how the body's immune defenses can be harnessed to promote the effectiveness of cytotoxic anti-cancer therapies. The ability of ionizing radiation to elicit anti-cancer immune responses capable of controlling tumor growth has led to the emergence of promising combination-based radio-immunotherapeutic strategies for the treatment of cancer. Herein we review the immunoadjuvant properties of localized radiation therapy and discuss how technological advances in radio-oncology and developments in the field of tumor-immunotherapy have started to revolutionize the therapeutic application of radiotherapy. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer Letters 01/2015; 368(2). DOI:10.1016/j.canlet.2015.01.009 · 5.62 Impact Factor
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