Asha.S and K.Bhagyalakshmi et al.

/ Journal of Pharmacy Research 2011,4(10),3829-3832

Review Article ISSN: 0974-6943

Available online through www.jpronline.info

Heat Shock Proteins

Asha.S and K.Bhagyalakshmi Division of Pharmacy, Department of Biochemistry,SriVenkateswaraUniversity,Tirupathi-517501, Chittoor Dist, Andhra Pradesh, INDIA

Received on: 19-06-2011; Revised on: 08-07-2011; Accepted on:01-10-2011 ABSTRACT

Heat shock proteins are the proteins that are present in all cells in all lifeforms from bacteria to humans.These get activated when cell undergoes environmental stresses like temperature fluctuations,oxygen demand and others.heir expression is transcriptionally regulated.

Key words: HSPs,chaperons,ATPases,Polypeptides,Prokaryotic,Eukaryotic

INTRODUCTION All organisms exhibit homeostatic-like responses when subjected to rapid changes in their environment. The ability of the organism to successfully adapt or acclimate to its new environment is critical to its survival, and likely represents an integral driving force in evolution. One well studied response to sudden adverse environmental changes is the so-called heat shock or stress response. When confronted with physiologically relevant increases in temperature, cells from all organisms respond similarly by rapidly increasing the synthesis of a select group of proteins, the heat shock.In addition to increased temperatures, other insults also result in increased HSP expression. These include exposure of cells to various metals, amino acid analogues, hypoxia, and a large number of agents/treatments which result in reduced ATP levels. Because so many adverse conditions lead to increased Hsp expression, the heat shock response now is commonly referred to as the stress response. Despite their designation as Hsps or stress proteins we now know that almost all of these proteins are in fact synthesized in cells grown under normal conditions (i.e. constitutive) and that their expression increases after metabolic stress. DEFINITION Heat shock proteins (HSPs), also called stress proteins, are a group of proteins that are present in all cells in all life forms. They are induced when a cell undergoes various types of environmental stresses like heat, cold and oxygen deprivation (Or)Heat shock proteins (HSP) are a class of functionally related proteins whose expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcription ally regulated. The dramatic up regulation of the heat shock proteins is a key part of the heat shock response and is induced primarily by heat shock factor (HSF). HSPs are found in virtually all living organisms, from bacteria to humans. DESCRIPTION Whenever a cell any cell, in any organism is stressed by heat, cold, or glucose or oxygen deprivation, HSPs are induced. In fact, the members of this family of dozens of related proteins account for an astounding 20 percent of a stressed cells soluble protein contents. HSPs abound even under perfectly tranquil conditions, when they comprise on the order of 2 percent of the cells contents., HSPs are involved not only in nursing proteins back to conformational health when they droop, but in other chaperone functions as well: midwifing newborn proteins into the proper

conformation to begin with; hustling them around among the cytosolic compartments; and, when theyre irredeemably bent out of shape, carting them off to intracellular garbage disposals to be degraded into the short chains of amino acids called peptides. Another key role of HSPs is on MHC. A loaded MHC molecule heads for the cell surface, where it can be monitored by roving sentry cells of the immune system that react vigorously if they sense any peptides that shouldnt be there for instance, fragments of viral proteins or of altered constituents of a cancerous cell. The similarity between a humans HSPs and those of a mouse is greater than 95 percent. Even bacterial HSPs bear something like a 50 percent homology to ours.All the roles just described for HSPs have been intracellular. They are essentially confined to a healthy cells cytosol and other intracellular compartments. Given HSPs role as all-purpose cellular chaperones, its not surprising that they would excel at grabbing onto peptides, nor that they would do so rather promiscuously. Between them all, HSPs are believed to bind about every conceivable peptide, regardless of size, composition or water- vs. fat-solubility.Heat shock proteins trigger immune response through activities that occur both inside the cell (intracellular) and outside the cell (extracellular).. Extracellular activities Heat shock proteins are normally found inside cells. When they are found outside the cell, it indicates that a cell has become so sick that it has died and spilled out all of its contents. This kind of messy, unplanned death is called necrosis, and only occurs when something is very wrong with the cell. Extracellular HSPs are one of the most powerful ways of sending a danger signal to the immune system in order to generate a response that can help to get rid of an infection or disease Versatile Escorts HSPs tend to associate with a wide range of client proteins, allowing the HSPs to perform a dizzying array of jobs. These can include helping newly formed amino acid chains to fold into their proper protein shapes, dismantling them after they have been damaged, escorting proteins to their intended mates and keeping them away from interlopers. Newly formed chains of amino acids are subject to various forces that help them to take on the right conformation. Each amino acid, for instance, has a characteristic response to water in the cellular cytoplasm. Hydrophobic amino acids abhor water and try to get away from it by nestling inside the protein structure, whereas hydrophilic amino acids prefer to face outward. Such mechanisms are not always enough to ensure proper folding, though, so HSPs, such as HSP60, get involved. HSP60 chaperone, which resembles a cage composed of multiple HSP60 molecules. Its inner rim is highly hydrophobic and therefore attracts the exposed hydrophobic amino acids of an unfolded protein to bind to it. Once such a chain is drawn into this cage, it encounters a hydrophilic interior, which the hydrophobic amino acids want to avoid at all costs, so the trapped molecule is

*Corresponding author.
Asha.S & K.Bhagyalakshmi, Division of Pharmacy, Department of Biochemistry, Sri Venkateswara University, Tirupathi-517501, Chittoor Dist, Andhra Pradesh. Tel.: + 91-: 9989628300, 8374837403 E-mail::ashkutti789@gmail.com, kbl_286@yahoo.co.in

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forced to change shape. This process may not happen in one go, and the cage may release and recapture the protein multiple times before the protein acquires a correctly folded conformation. Thus, the HSP60 protein is known as a folds. Conversely, the HSP100 protein is an unfolds. It, too, is a multisubunit ring, which, in cooperation with HSP70, can disassemble damaged proteins or undesirable protein aggregates or can even cause a fully folded protein to unfold. In contrast to the cagelike chaperones, most HSPs do not enclose their substrates but rather grab them by the elbows to help them along. HSP70, for example, binds directly to short stretches of amino acid sequences, also known as peptides. The molecule has a peptide-binding cleft that is open when HSP70 is bound to the cellular energy source ATP, but when ATP is absent, a lidlike structure on HSP70 clamps down on the bound peptide and traps the larger protein chain in place.The ability of HSP70 to grab a variety of different peptides allows the molecule to play chaperone in many fundamental cellular processes, such as helping new amino acid chains to assume a mature conformation, facilitating the assembly of complex proteins and protecting proteins from falling apart in high temperatures. Although heat shock proteins are active in cells in normal circumstances, it is easy to see how their help would be even more valuable to a cell in a difficult situation. Under emergency conditions, such as extreme heat or cold, oxygen deprivation, dehydration or starvation, a cell would be struggling just to survive. Critical proteins might be degraded by the harsh environment, even as the cell would try to churn out replacements. In these circumstances, heat shock proteins would mitigate the stress by rescuing essential proteins, dismantling and recycling damaged ones, and generally keeping cell operations running as smoothly as possible. Hence, when a cell is under high stress, one of its first responses will be to manufacture more of the HSPs themselves DISCOVERY It is known that rapid heat hardening can be elicited by a brief exposure of cells to sub-lethal high temperature, which in turn provides protection from subsequent and more severe temperature. In 1962, Ritossa reported that heat and the metabolic inhibitor dinitrophenol induced a characteristic pattern of puffing in the chromosomes of Drosophila. This discovery eventually led to the identification of the heat-shock proteins (HSP) or stress proteins whose expression these puffs represented. Increased synthesis of selected proteins in Drosophila cells following stresses such as heat shock was first reported in 1974. Beginning in the mid-1980s, investigators recognized that many HSPs function as molecular chaperones and thus play a critical role in protein folding, intracellular trafficking of proteins, and coping with proteins denatured by heat and other stresses. Accordingly, the study of stress proteins has undergone explosive growth CLASSIFICATION The principal heat-shock proteins that have chaperone activity belong to five conserved classes: HSP33,HSP60, HSP70, HSP90, HSP100, and the small heat-shock proteins (sHSPs).
Approximate molecular weight(kDa) 10 kDa 20-30 kDa 40 kDa 60 kDa 70 kDa Prokaryotic proteins GroES GrpE DnaJ GroEL, 60kDa antigen DnaK Eukaryotic proteins Hsp10 The HspB group of Hsp. Ten members in mammals including Hsp27 or HspB1 Hsp40 Hsp60 The HspA group of Hsp including Hsp71, Hsp70, Hsp72, Grp78 (BiP), Hsx70 found only in primates Function

Hsp60 use ATP to control binding and dissociation of substrate polypeptides. Crystal structures of Hsp70 and Hsp60 reveal differences in mechanism. Hsp70 Hsp70 proteins contain two domains, an amino-terminal ATPase domain and a carboxy-terminal peptide-binding domain. The secondary and tertiary structure of the ATPase domain is almost identical to that of actin. The Hsp70 peptidebinding domain binds a seven-residue peptide in an extended conformation between a beta-sheet subdomain and alpha-helical subdomain. Two or three hydrophobic residues of the peptide are buried in pockets of the beta subdomain, and peptide backbone NH and CO groups form hydrogen bonds with sidechain and backbone groups on the beta subdomain. The ends of the substrate peptide extend out from either side of the peptide-binding domain. The alpha domain clamps down loops of the beta subdomain, pinning the peptide in place. It is thought that ATP binding to the ATPase domain triggers substrate release by causing the alpha domain to bend upwards at a flexible junction near the middle of the long helix that extends over the peptide.The peptide-binding domain of E. coli Hsp70 (DnaK). The substrate peptides shown in black. For a better look, view the structure 1dkx.pdb using Rasmol.

Hsp60 Hsp60 is somewhat more complicated because its oligomeric structure is a critical feature of its mechanism. Hsp60 proteins are composed of 14 subunits arranged in two stacked 7-membered rings. An unfolded protein binds to large hydrophobic surfaces inside the central cavity. ATP binding triggers rotation of the Hsp60 subunits such that the hydrophobic surface turns toward the neighboring Hsp60 subunit. This conformational change is coordinated around the ring by binding of Hsp10 which closes the cavity with the substrate inside. Perhaps this creates a chamber for the protein to fold without the possibility of aggregation with other unfolded proteins. E. coli Hsp60 (GroEL) top view. C-alpha trace colored by crystallographic B-factors. Red indicates high mobility; blue low mobility. The inside of the apical domains, where unfolded substrates are thought to bind, are the most mobile.

90 kDa 100 kDa

HtpG, C62.5 ClpB, ClpA, ClpX

The HspC group of Hsp including Hsp90, Grp94 Hsp104, Hsp110

Co-factor of Hsp70 Involved in protein folding after its post-translational import to the mitochondrion/chloroplast Protein folding and unfolding, provides thermotolerance to cell on exposure to heat stress. Also prevents protein folding during posttranslational import into the mitochondria/chloroplast. Maintenance of steroid receptors and transcription factors Tolerance of extreme temperature

Although the most important members of each family are tabulated here, it should be noted that some species may express additional chaperones, cochaperones, and heat shock proteins not listed. Additionally, many of these proteins may have multiple splicevariants (Hsp90a and Hsp90, for instance) or conflicts of nomenclature (Hsp72 is sometimes called Hsp70). All molecular chaperones recognize hydrophobic features of unfolded substrate polypeptides, thereby discriminating against folded proteins. Both Hsp70 and

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d) Cardiovascular Heat shock proteins appear to serve a significant cardiovascular role. Hsp90, hsp84, hsp70, hsp27, hsp20, and alpha-B-crystallin all have been reported as having roles in the cardiovasculature.Hsp90 binds both endothelial nitric oxide synthase and soluble guanylate cyclase which in turn are involved in vascular relaxationA downstream kinase of the nitric oxide cell signalling pathway, protein kinase G, phosphorylates a small heat shock protein, hsp20. Hsp20 phosphorylation correlates well with smooth muscle relaxation and is one significant phosphoprotein involved in the process. Hsp20 appears significant in development of the smooth muscle phenotype during development. Hsp20 also serves a significant role in preventing platelet aggregation, cardiac myocyte function and prevention of apoptosis after ischemic injury, and skeletal muscle function and muscle insulin response. Hsp27 is a major phosphoprotein during muscle contraction. Hsp27 functions in smooth muscle migration and appears to serve an integral role. FUNCTIONS a)Upregulation in stress Production of high levels of heat shock proteins can also be triggered by exposure to different kinds of environmental stress conditions, such as infection, inflammation, exercise, exposure of the cell to toxins (ethanol, arsenic, trace metals and ultraviolet light, among many others), starvation, hypoxia (oxygen deprivation), nitrogen deficiency (in plants), or water deprivation. Consequently, the heat shock proteins are also referred to as stress proteins and their upregulation is sometimes described more generally as part of the stress response. The mechanism by which heat-shock (or other environmental stressors) activates the heat shock factor has not been determined. However, some studies suggest that an increase in damaged or abnormal proteins brings HSPs into action. b) Role as chaperone Heat shock proteins function as intra-cellular chaperones for other proteins. They play an important role in protein-protein interactions such as folding and assisting in the establishment of proper protein conformation (shape) and prevention of unwanted protein aggregation. By helping to stabilize partially unfolded proteins, HSPs aid in transporting proteins across membranes within the cell.Some members of the HSP family are expressed at low to moderate levels in all organisms because of their essential role in protein maintenance. Heat Shock Proteins and Molecular Chaperones Most, but not all, heat shock proteins are molecular chaperones. Molecular chaperones bind and stabilize proteins at intermediate stages of folding, assembly, translocation across membranes and degradation. Heat shock proteins have been classified by molecular weight, for example, Hsp70 for the 70 kDa heat shock protein. Hsp70 null mutants of E. coli cannot grow at elevated temperature. Hsp100 null fruit flies lose their capacity for acquired thermotolerance. Heat shock proteins are among the most well-conserved proteins known. Amino acid sequences for Hsp70s of E. coli and man are almost 50% identical. Hsp functions are required at normal temperatures, but the level of expression is reduced, and the identity of the Hsp may be different. In E. coli , Hsp70 is expressed at much reduced level in unstressed conditions, but it plays an important role in export of proteins to the periplasm and in protein degradation. In yeast, there are 13 different Hsp70 proteins. The heat-induceable version of yeast cytosolic Hsp70 is not expressed at normal temperatures, but a constitutively expressed heat shock protein cognate (Hsc70) participates in protein translocation across membranes and other functions.
Heat Shock Protein Hsp100 Hsp90 Cohorts ? Immunophilins, Hsp70, others Function, etc. ATPse; dissociates aggregates, facilitates proteolysis; essential in yeast for acquired thermotolerance; essential for yeast prion propagation stabilizes proteins prior to complete folding or activation; forms stable complexes with inactive glucocorticoid receptor and other transcription factors; most abundant non-ribosomal protein (cytosolic version); most abundant protein in endoplasmic reticulum (ER version) ATPase; stabilizes proteins prior to complete folding, transport across membranes and proteolysis; found associated with misfolded and unassembled proteins, e.g., mutant p53 in cytosol or immunoglobulin heavy chains in ER of cells that dont make light chains; homologs in mitochondria and chloroplasts ATPase; promotes efficient folding; only in mitochondria and chloroplasts of eukaryotes; distant homolog in cytosol is specialized for folding actin and tubulin; a.k.a., chaperonin blocks aggregation; involved in regulation of actin assembly/disassembly

e)Immunity Extracellular and membrane bound heat-shock proteins, especially Hsp70 are involved in binding antigens and presenting them to the immune system. v The Heat Shock Response

Acquired Thermotolerance In response to many stresses, including heat, oxidizing conditions, and exposure to toxic compounds, all cells produce a common set heat shock proteins (Hsps). Experiments in E. coli, yeast, fruit flies and mice have shown that increased expression of these proteins can protect the organism against stress-induced damage. The classic phenomenon of acquired thermotolerance led to the identification of the major classes of heat shock proteins in E. coli. Cells given a non-lethal preshock at 42 oC subsequently survive an otherwise lethal exposure to 46 oC. The preshocked cells stopped synthesis of the normal spectrum of proteins and began to synthesize a few proteins at high level.

A very similar response occurs in all organisms. Increased expression of Hsps is mediated at multiple levels, mRNA synthesis, mRNA stability, and translation efficiency. Elevated synthesis of Hsps persists only through the initial period of stress. Even if the organism continues to be exposed to high temperature after the initial shock, Hsp expression drops, and Hsp levels return to normal. The heat shock response is distinct from adaptive responses that an organism may undergo when its environment changes gradually. APPLICATIONS a)Cancer vaccine adjuvant Given their role in antigen presentationHSPs are useful as immunologic adjuvants in boosting the response to a vaccine. Furthermore, some researchers speculate that HSPs may be involved in binding protein fragments from dead malignant cells and presenting them to the immune system. Therefore HSPs may be useful for increasing the effectiveness of cancer vaccines. b)Anticancer therapeutics Intracellular heat shock proteins are highly expressed in cancerous cells and are

Hsp70

Hsp40

Hsp60 Hsp25

Hsp10 ?

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essential to the survival of these cell types. Hence small molecule inhibitors of Hsps, especially Hsp90 show promise as anticancer agents. The potent Hsp90 inhibitor 17-AAG is currently in clinical trials for the treatment of several types of cancer. c)Agricultural Researchers are also investigating the role of HSPs in conferring stress tolerance to hybridized plants, hoping to address drought and poor soil conditions for farming. HEAT SHOCK PROTEINS AND DISEASE Despite the obvious importance of stress responses, only recently has scrutiny focused on the role of heat shock proteins in the control of disease pathology and in the survival and virulence of pathogens. Knowlege about Hsp functions in bacteria is much further advanced than in eukaryotes, but already some hints of Hsp involvement in mammalian diseases have emerged. Here is a list of phenomena. Viral infection induces Hsp expression Bacterial viruses use Hsps to facilitate takover of the cellular DNA replication machinery, and they employ Hsps for assembly of virus particles. In eukaryotes, heat shock proteins associate with key viral products, such as simian virus 40 (SV40) T-antigen, that control cell cycle progression and cause tissue transformation (cancer). Oxidative stress induces Hsp expression. Immune cells release nitric oxide and superoxide in the attack on invading cells. Host cells express Hsps to protect against oxidative damage. Unfortunately, the pathogens also mount a protective response with massive overproduction of Hsps. Hsp70 conveys peptide antigens for presentation to the immune system. Similar to its role in delivery of newly-synthesized proteins to the mitochondrion and ER, Hsp70 delivers peptides to the endoplasmic reticulum and proteins to the lysosome. Peptides generated by the proteasome in the cytoplasm are transported through the ER membrane via TAP transporters, loaded into class I major histocompatibility (MHC) proteins, and presented to CD8 cytotoxic T-cells. Peptides generated by acid hydrolases in the lysosomes are loaded into class II MHC proteins and presented to CD4 helper T-cells. Hsps are immunodominant antigens. Since they are so abundantly expressed, Hsps swamp the immune system with epitopes. Despite that they are highly conserved proteins, sufficient sequence divergence allows the mammalian immune system to avoid tolerance of Hsps. In some cases, anti-Hsp responses are protective. In other cases, anti-Hsp responses are thought to initiate or propagate autoimmune disease by crossreacting with self Hsps. In still other cases, a response against self Hsp (Hsp60) paradoxically suppresses autoimmune disease symptoms! Emotional as well as mechanical stresses induce Hsp expression. When rats are physically restrained, their vascular endothelial cells express elevated levels of Hsp70. The response has been linked to an abrupt increase in blood pressure. Elevated Hsp70 expression protects against cardiac failure. Hearts of transgenic mice that express elevated Hsp70 sustain less damage as a result of an experimental ischemic event.Hsp100 is necessary for propagation of prions in yeast.Aggregates of the Sup35 protein propagate themselves in a reaction that depends on yeast Hsp100. Although mammalian prions are composed of an unrelated protein, experiments with transgenic mice suggest that the species barrier is at least partly imposed by interactions between the prion proteins and a host factor that could be a molecular chaperone.Neurons are acutely sensitive to stress, possibly because they exhibit little or no stress response.In contrast, glia and other non-neuronal cells exhibit a robust stress response. Some evidence indicates that a specific mechanism transports Hsps from support cells to neurons during stress. MARKETED PRODUCTS AND DRUGS UNDER CLINICAL TRIALS The Antigenics investigational HSPbased cancer vaccine Oncophage is autologous, meaning it is derived directly from and created specifically for each individual patient. This patient-specific approach is designed to treat with extreme precision an enormously variable disease that differs not only from cancer to cancer, but also from person to person. By isolating HSP complexes from a patients tumor, the vaccines are meant to capture the specific cancers fingerprint in order to program the immune system to target any cells and only those cells that bear this fingerprint. Antigenics is also evaluating HSP technology in nonautologous applications. By complexing recombinantly derived HSPs and common viral proteins, Antigenics AG-707 genital herpes immunotherapeutic product is intended to target only infected cells, which bear these viral proteins. HSP technology was designed to allow extreme specificity in cancer and infectious disease treatment, thereby preserving healthy tissue VACCINATING AGAINST CANCER Kidney cancer Melanoma Pancreatic cancer REFERENCES
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Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.4.Issue 10. October 2011

3829-3832