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
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.
Available from: Walter Manucha
- "Also, they protect nascent translating proteins, promote the organellar transport of proteins and reduce toxic aggregates. The inducible HSP 72 and 73 kDa forms are found at the highest level[104,105]. Protein folding regulated by HSP70 is a complex ATP/ADP-dependent process. HSP expression is regulated in multiple organs during de- velopment. "
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ABSTRACT: Insulin resistance (IR) is present in pathologies such as diabetes, obesity, metabolic syndrome, impaired glucose tolerance, hypertension, inflammation, cardiac disease, and dyslipidemias. Population studies show that IR is multifactorial and has genetic components, such as defects in the insulin-signaling pathway (as serine phosphorylation on insulin substrate or decreased activation of signaling molecules) and RAS/MAPK-dependent pathways. IR is connected to mitochondrial dysfunction, overproduction of oxidants, accumulation of fat, and an over-activation of the renin-angiotensin system linked to the NADPH oxidase activity. In addition, nitric oxide (NO), synthesized by nitric oxide synthases (endothelial and inducible), is also associated with IR when both impaired release and reduced bioavailability of all which lead to inflammation and hypertension. However, increased NO may promote vasculoprotection. Moreover, reduced NO release induces heat shock protein 70 kDa (HSP70) expression in IR and diabetes, mediating beneficial effects against oxidative stress injury, inflammation and apoptosis. HSP70 may be used as biomarker of the chronicity of diabetes. Hsp72 (inducible protein) is linked to vascular complications with a high-fat diet by blocking inflammation signaling (cytoprotective and anti-cytotoxicity intracellular role). Elucidating the IR signaling pathways and the roles of NO and HSPs is relevant to the application of new treatments, such as heat shock and thermal therapy, nitrosylated drugs, chemical chaperones or exercise training.
- "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.
Available from: Mj Freitas
- "These proteins can be activated by a variety of endogenous and exogenous factors (Middendorff et al., 2000; Piotrkowski et al., 2009). HSPs enhance cell survival in response to stress, such as oxidative stress, since they are capable of attenuating the toxicity of denatured and misfolded proteins that are accumulated during stress (Murphy, 2013). Sirtuin 1 (SIRT1) is a NAD-dependent deacetylase that inhibits p53, thereby preventing apoptotic events. "
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ABSTRACT: Exercise and physical activity have long been recognized for health promotion and to delay the onset of many pathological situations such as diabetes and cancers. Still, there appears to be an upper limit on the beneficial health effects regarding intensity and frequency of exercise training. In humans, the effect of exercise training in the male reproductive system has been studied mainly through the analysis of semen quality parameters, with inconsistent results. Less is known on molecular biomarkers of exercise-related changes in testis at the protein/proteome level. This review offers an in-depth analysis on the small scale protein studies available primarily from the preclinical studies and interprets their functional impact on the reproductive health with a view to humans. In all, exercise training in preclinical models seems to negatively modulate, in the course of health, critical functions that directly affect spermatogenesis, such as testosterone biosynthesis, energy supply, and antioxidant system components. Exercise training induces apoptosis, leading to the impairment of spermatogenesis and, consequently, to male infertility. In pathological conditions, an improvement in the testicular functions is observed by increases in steroidogenic enzymes and antioxidant defenses, and reductions in activity of inflammatory pathways. Importantly, the mechanisms by which exercise training modulates the reproductive function are far from being fully understood. The analyses of the testis proteome in varying exercise conditions would inform the molecular mechanisms involved and identify putative theranostics opportunities. Such future research is a cornerstone for health promotion in the pursuit of reproductive health informed by omics systems sciences.
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