Molecular chaperones and the stress of oncogenesis (original) (raw)
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Role of the heat shock response and molecular chaperones in oncogenesis and cell death
Journal of the National Cancer …, 2000
Exposure of cells to conditions of environmental stressincluding heat shock, oxidative stress, heavy metals, or pathologic conditions, such as ischemia and reperfusion, inflammation, tissue damage, infection, and mutant proteins associated with genetic diseases-results in the inducible expression of heat shock proteins that function as molecular chaperones or proteases. Molecular chaperones are a class of proteins that interact with diverse protein substrates to assist in their folding, with a critical role during cell stress to prevent the appearance of folding intermediates that lead to misfolded or otherwise damaged molecules. Consequently, heat shock proteins assist in the recovery from stress either by repairing damaged proteins (protein refolding) or by degrading them, thus restoring protein homeostasis and promoting cell survival. The events of cell stress and cell death are linked, such that molecular chaperones induced in response to stress appear to function at key regulatory points in the control of apoptosis. On the basis of these observations-and on the role of molecular chaperones in the regulation of steroid aporeceptors, kinases, caspases, and other protein remodeling events involved in chromosome replication and changes in cell structure-it is not surprising that the heat shock response and molecular chaperones have been implicated in the control of cell growth. In this review, we address some of the molecular and cellular events initiated by cell stress-the interrelationships between stress signaling, cell death, and oncogenesis-and chaperones as potential targets for cancer diagnosis and treatment. [
Heat shock proteins in human cancer
Electrophoresis, 2000
The heat shock proteins (hsp) are ubiquitous molecules induced in cells exposed to sublethal heat shock, present in all living cells, and highly conserved during evolution. Their function is to protect cells from environmental stress damage by binding to partially denatured proteins, dissociating protein aggregates, to regulate the correct folding, and to cooperate in transporting newly synthesized polypeptides to the target organelles. The molecular chaperones are involved in numerous diseases, including cancer, revealing changes of expression. In this review, we mainly describe the relationship of hsp expression with human cancer, and discuss what is known about their post-translational modifications according to malignancies.
Translationally controlled tumor protein is a novel heat shock protein with chaperone-like activity
Biochemical and Biophysical Research Communications, 2009
tumor protein (TCTP) is often designated as a stress-related protein because of 21 its highly regulated expression in stress conditions. Following a thermal shock, TCTP expression is highly 22 upregulated in a variety of cells. However, at present it is not known whether this upregulation has any 23 cell protective function similar to other heat shock proteins. In this study human TCTP (HuTCTP) and a 24 TCTP homolog (SmTCTP) from Schistosoma mansoni were evaluated for heat shock protein-like function and molecular chaperone activity. Our results show that similar to other molecular chaperones, both 26 human and parasite TCTPs can bind to a variety of denatured proteins and protect them from the harmful 27 effects of thermal shock. An important observation was the ability of both HuTCTP and SmTCTP to bind to 28 native protein and protect them from thermal denaturation. Over expression of TCTP in bacterial cells 29 protected them from heat shock-induced death. These findings suggest that TCTP may belong to a novel 30 small molecular weight heat shock protein.
Heat shock proteins as novel therapeutic targets in cancer
In vivo (Athens, Greece)
Heat shock proteins (HSPs) are evolutionarily conserved molecules synthesised by cells exposed to sub-lethal stresses. Acting as molecular chaperones, HSPs protect cells from environmental stress damage by assisting in proper folding and stabilisation of proteins. In addition, they help to sequester severely damaged proteins for degradation. Owing to the nature of their function, HSPs are often found to be overexpressed in a wide range of cancers. Members of the HSP family have been implicated in cancer growth as promoting tumour cell proliferation as well as inhibiting cellular death pathways. In recent years, several HSP90 client proteins have been validated as clinically important therapeutic targets for treatment of cancer, and inhibitors of HSP90 have emerged as potentially beneficial anticancer agents. This review explores the involvement of HSPs in cancer and the development of several anticancer agents with promising therapeutic applications.
Journal of applied physiology (Bethesda, Md. : 1985), 2002
Heat shock of mammalian cells causes protein damage and activates a number of signaling pathways. Some of these pathways enhance the ability of cells to survive heat shock, e.g., induction of molecular chaperones [heat shock protein (HSP) HSP72 and HSP27], activation of the protein kinases extracellular signal-regulated kinase and Akt, and phosphorylation of HSP27. On the other hand, heat shock can activate a stress kinase, c-Jun NH2-terminal kinase, thus triggering both apoptotic and nonapoptotic cell death programs. Recent data indicate that kinases activated by heat shock can regulate synthesis and functioning of the molecular chaperones, and these chaperones modulate activity of the cell death and survival pathways. Therefore, the overall balance of the pathways and their interplay determine whether a cell exposed to heat shock will die or survive and become stress tolerant.
Heat shock proteins as emerging therapeutic targets
British Journal of Pharmacology, 2005
Chaperones (stress proteins) are essential proteins to help the formation and maintenance of the proper conformation of other proteins and to promote cell survival after a large variety of environmental stresses. Therefore, normal chaperone function is a key factor for endogenous stress adaptation of several tissues. However, altered chaperone function has been associated with the development of several diseases; therefore, modulators of chaperone activities became a new and emerging field of drug development. Inhibition of the 90 kDa heat shock protein (Hsp)90 recently emerged as a very promising tool to combat various forms of cancer. On the other hand, the induction of the 70 kDa Hsp70 has been proved to be an efficient help in the recovery from a large number of diseases, such as, for example, ischemic heart disease, diabetes and neurodegeneration. Development of membrane-interacting drugs to modify specific membrane domains, thereby modulating heat shock response, may be of considerable therapeutic benefit as well. In this review, we give an overview of the therapeutic approaches and list some of the key questions of drug development in this novel and promising therapeutic approach.