Heat shock protein

Heat shock proteins (HSPs) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock,[1] but are now known to also be expressed during other stresses including exposure to cold,[2] UV light[3] and during wound healing or tissue remodeling.[4] Many members of this group perform chaperone functions by stabilizing new proteins to ensure correct folding or by helping to refold proteins that were damaged by the cell stress.[5] This increase in expression is transcriptionally regulated. The dramatic upregulation of the heat shock proteins is a key part of the heat shock response and is induced primarily by heat shock factor (HSF).[6] HSPs are found in virtually all living organisms, from bacteria to humans.

Heat shock proteins are named according to their molecular weight. For example, Hsp60, Hsp70 and Hsp90 (the most widely studied HSPs) refer to families of heat shock proteins on the order of 60, 70 and 90 kilodaltons in size, respectively.[7] The small 8-kilodalton protein ubiquitin, which marks proteins for degradation, also has features of a heat shock protein.[8] A conserved protein binding domain of approximately 80 amino-acid alpha crystallins are known as small heat shock proteins (sHSP).[9]

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, Italian geneticist Ferruccio Ritossa reported that heat and the metabolic uncoupler 2,4-dinitrophenol induced a characteristic pattern of "puffing" in the chromosomes of Drosophila.[1][10] This discovery eventually led to the identification of the heat-shock proteins (HSP) or stress proteins whose expression this puffing represented. Increased synthesis of selected proteins in Drosophila cells following stresses such as heat shock was first reported in 1974.[11] In 1974, Tissieres, Mitchell and Tracy[12] discovered that heat-shock induces the production of a small number of proteins and inhibits the production of most others. This initial biochemical finding gave rise to a large number of studies on the induction of heat shock and its biological role. Heat shock proteins often function as chaperones in the refolding of proteins damaged by heat stress. Heat shock proteins have been found in all species examined, from bacteria to humans, suggesting that they evolved very early and have an important function.

Function

According to Marvin et al. sHSPs independently express not only in heat shock response but also have developmental roles in embryonic or juvenile stages of mammals, teleost fish and some lower vertebral genomes. hspb1 (HSP27) is expressed during stress and during the development of embryo, somites, mid-hindbrain, heart and lens in zebrafish. Expression of the hspb4 gene, which codes for alpha crystallin, increases considerably in the lens in response to heat shock.[13]

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 harmful materials (ethanol, arsenic, and trace metals, among many others), ultraviolet light, starvation, hypoxia (oxygen deprivation), nitrogen deficiency (in plants) or water deprivation. As a consequence, 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.[14]

The mechanism by which heat-shock (or other environmental stressors) activates the heat shock factor has been determined in bacteria. During heat stress, outer membrane proteins (OMPs) do not fold and cannot insert correctly into the outer membrane. They accumulate in the periplasmic space. These OMPs are detected by DegS, an inner membrane protease, that passes the signal through the membrane to the sigmaE transcription factor.[15] However, some studies suggest that an increase in damaged or abnormal proteins brings HSPs into action.

Some bacterial heat shock proteins are upregulated via a mechanism involving RNA thermometers such as the FourU thermometer, ROSE element and the Hsp90 cis-regulatory element.[16]

Petersen and Mitchell[17] found that in D. melanogaster a mild heat shock pretreatment which induces heat shock gene expression (and greatly enhances survival after a subsequent higher temperature heat shock) primarily affects translation of messenger RNA rather than transcription of RNA. Heat shock proteins are also synthesized in D. melanogaster during recovery from prolonged exposure to cold in the absence of heat shock.[18] A mild heat shock pretreatment of the same kind that protects against death from subsequent heat shock also prevents death from exposure to cold.[18]

Role as chaperone

Several 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.[19][20]

Some members of the HSP family are expressed at low to moderate levels in all organisms because of their essential role in protein maintenance.

Management

Heat-shock proteins also occur under non-stressful conditions, simply "monitoring" the cell's proteins. Some examples of their role as "monitors" are that they carry old proteins to the cell's "recycling bin" (proteasome) and they help newly synthesised proteins fold properly.

These activities are part of a cell's own repair system, called the "cellular stress response" or the "heat-shock response".

Recently, there are several studies that suggest a correlation between HSPs and dual frequency ultrasound as demonstrated by the use of LDM-MED machine.

Heat shock proteins appear to be more susceptible to self-degradation than other proteins due to slow proteolytic action on themselves.[21]

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.[22]

Hsp90 binds both endothelial nitric oxide synthase and soluble guanylate cyclase, which in turn are involved in vascular relaxation.[23]

The subset of hsp70, extracellular hsp70 (ehsp70) and intracellular hsp70 (ihsp70), has been shown to have a pivotal role in managing oxidative stress and other physiological factors.[24]

Krief et al. referred hspb7 (cvHSP - cardiovascular Heat shock protein) as cardiac heat shock protein. Gata4 is an essential gene responsible for cardiac morphogenesis. It also regulates the gene expression of hspb7 and hspb12. Gata4 depletion can result in reduced transcript levels of hspb7 and hspb12 and this could result in cardiac myopathies in zebrafish embryos as observed by Gabriel et al.[25]

hspb7 also acts in the downregulation of Kupffer vesicles which is responsible for regulation of left-right asymmetry of heart in zebrafish. Along with hspb7, hspb12 is involved in cardiac laterality determination.[9] A 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.[26] 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.[27]

Hsp27 is a major phosphoprotein during women's contractions. Hsp27 functions in small muscle migrations and appears to serve an integral role.[28]

Immunity

Function of heat-shock proteins in immunity is based on their ability to bind not only whole proteins, but also peptides. The affinity and specificity of this interaction is typically low.[29]

It was shown, that at least some of the HSPs possess this ability, mainly hsp70, hsp90, gp96 and calreticulin, and their peptide-binding sites were identified.[29] In the case of gp96 it is not clear whether it can bind peptides in vivo, although its peptide-binding site has been found.[30] But gp96 immune function could be peptide-independent, because it is involved in proper folding of many immune receptors, like TLR or integrins.[29]

Apart from that, HSPs can stimulate immune receptors and are important in proper folding of proteins involved in pro-inflammatory signaling pathways.[30][31]

Antigen presentation

HSPs are indispensable components of antigen presentation pathways - the classical ones[29][32][33] and also cross-presentation[30] and autophagy.[33]

MHCI presentation

In the simplified view of this pathway HSPs are usually not mentioned: antigenic peptides are generated in proteasome, transported into ER through protein transporter TAP and loaded onto MHCI, which then goes through secretory pathway on plasma membrane.

But HSPs play an important part in transfer of unfolded proteins to proteasome and generated peptides to MHCI.[29] Hsp90 can associate with proteasome and take over generated peptides. Afterwards, it can associate with hsp70, which can take the peptide further to the TAP. After passing through TAP, ER chaperons are getting important - calreticulin binds peptides and together with gp96 form peptide loading complex for MHCI.

This handing over with peptides is important, because HSPs can shield hydrophobic residues in peptides which would be otherwise problematic in aquatic cytosol. Also simple diffusion of peptides would be too ineffective.[29]

MHCII presentation

In MHCII presentation, HSPs are involved in clathrin-dependent endocytosis.[33] Also when HSPs are extracellular, they can guide their associated peptides into MHCII pathway, although it is not known how they are distinguished from the cross-presented ones (see below).[30]

Autophagy

HSPs are involved in classical macroautophagy, when protein aggregates are enclosed by double membrane and degraded afterwards.[33] They are also involved in a special type of autophagy called chaperone-mediated autophagy, when they enable cytosolic proteins to get into lysosomes.[33]

Cross-presentation

When HSPs are extracellular, they can bind to specific receptors on dendritic cells (DC) and promote cross-presentation of their carried peptides. The most important receptors in this case are scavenger receptors, mainly SRECI and LOX-1.[30] CD91 scavenger receptor has been previously proposed as the common HSP receptor. But now its relevance is controversial because the majority of DC types does not express CD91 in relevant amounts and the binding capacity for many HSPs has not been proved.[30] Stimulation of some scavenger receptors can even result in immunosuppression, this is the case for SRA.[30]

LOX-1 and SRECI when stimulated guide HSPs with their associated peptides into cross-presentation. LOX-1 binds mainly hsp60 and hsp70. SRECI is now considered to by the common heat-shock protein receptor because it binds hsp60, hsp70, hsp90, hsp110, gp96 and GRP170.[30]

The relevance for this type of cross-presentation is high especially in tumour-immunosurveillance.[30][29] Thanks to the HSP, the bound peptide is protected against degradation in dendritic cell compartments and the efficiency of cross-presentation is higher. Also internalisation of HSP-peptide complex is more efficient than internalisation of soluble antigens. Tumor cells usually express only a few neo-antigens, which can be targeted by immune system and also not all tumor cells express them. Because of that the amount of tumor antigens is restricted and high efficiency of cross-presentation is necessary for mounting strong immune response.

Hsp70 and hsp90 are also involved intracellulary in cytosolic pathway of cross-presentation where they help antigens to get from endosome into the cytosol.[29]

Damage-associated molecular patterns

Extracellular heat-shock proteins can be sensed by the immunity as damage-associated molecular patterns (DAMPs).[30] They are able to interact with pattern recognition receptors like TLR2 or TLR4 and activate antigen presenting cells by upregulation of co-stimulation molecules (CD80, CD86, CD40), MHC molecules and pro-inflammatory and Th1 cytokines.[29][32] HSP70 was shown to react to DAMP release, causing an influx of HSP70-positive T-EVs (tumor cells) that initiate anti-tumor immune signaling cascades.[34]

Heat-shock proteins can signal also through scavenger receptors, which can either associate with TLRs, or activate pro-inflammatory intracellular pathways like MAPK or NF-kB. With the exception of SRA, which down-regulates immune response.[29]

Transport into extracellular space

Heat-shock proteins can be secreted from immune cells or tumour cells by non-canonical secretion pathway, or leaderless pathway, because they do not have the leader peptide, which navigate proteins into endoplasmic reticulum. The non-canonical secretion can be similar to the one, which occurs for IL1b, and it is induced by stress conditions.[30]

Another possibility is release of HSPs during cell necrosis, or secretion of HSPs in exosomes.[30] During special types of apoptotic cell death (for example induced by some chemotherapeutics), HSPs can also appear on the extracellular side of plasma membrane.[32]

There is a debate about how long can HSP keep its peptide in extracellular space, at least for hsp70 the complex with peptide is quite stable.[30]

The role of extracellular HSPs can be miscellaneous. It depends a lot on context of tissue whether HSPs will stimulate the immune system or suppress immunity. They can promote Th17, Th1, Th2 or Treg responses depending on antigen-presenting cells.[29]

As a result, the clinical use of heat-shock proteins is both in cancer treatment (boosting an immune response) and treatment of autoimmune diseases (suppress of immunity).[35][29]

Lens

Alpha crystallin (α4- crystallin) or hspb4 is involved in the development of lens in Zebrafish as it is expressed in response to heat shock in the Zebrafish embryo in its developmental stages.[13]

Clinical significance

HSF 1

Heat shock factor 1 (HSF 1) is a transcription factor that is involved in the general maintenance and upregulation of Hsp70 protein expression.[36][37] Recently it was discovered that HSF1 is a powerful multifaceted modifier of carcinogenesis. HSF1 knockout mice show significantly decreased incidence of skin tumor after topical application of DMBA (7,12-dimethylbenzanthracene), a mutagen.[38] Moreover, HSF1 inhibition by a potent RNA aptamer attenuates mitogenic (MAPK) signaling and induces cancer cell apoptosis.[39]

Diabetes mellitus

Diabetes mellitus (DM) is a immune-disease characterized by the presence of hyperglycemia. Typically these symptoms are brought about by insulin deficiency.[40] However, there have been many recent articles alluding to a correlation between hsp70, in some cases hsp60, and DM.[41][42] Another recent article discovered the ratio of ehsp70 and ihsp70 could have an effect on DM, leading to a sufficient biomarker.[43] Serum levels of hsp70 have also been shown to increase over time in patients with diabetes.[44]

Cancer

HSP expression plays a pivotal role in cancer identification. Recent discoveries have shown that high concentrations of eHSP can indicate the presence of contentious tumors.[45] Additionally, HSPs have been shown to benefit oncologist in oral cancer diagnosis.[46] Using techniques such as dot immunoassay and ELISA test researchers have been able to determine that HSP-specific phage antibodies could be beneficial in-vitro cancer diagnosis markers.[47] HSPs have also been shown to interact with cancer adaptations such as drug resistance, tumor cell production and lifespan, and the up-regulation and down-regulation of oncomirs.[48]

Applications

Cancer vaccines

Given their role in presentation,[49] HSPs are useful as immunologic adjuvants (DAMPS) in boosting the response to a vaccine.[50] Furthermore, some researchers speculate that HSPs may be involved in binding protein fragments from dead malignant cells and presenting them to the immune system.[51] In a recent study published by Sedlacek et al., HSP was shown to effect different signaling pathways involved in carcinogenesis responses such as STAT1 activation, gp96-activated macrophages, and activation of NK cells.[52] Therefore, HSPs may be useful for increasing the effectiveness of cancer vaccines.[49][53]

Also isolated HSPs from tumor cells are able to act as a specific anti-tumor vaccine by themselves.[32][30] Tumour cells express a lot of HSPs because they need to chaperone mutated and over-expressed oncogenes, tumour cells are also in a permanent stress. When HSPs from a tumour are isolated, the peptide repertoire bound by HSPs is somewhat a fingerprint of these particular tumour cells. Application of such HSPs back into patient then stimulate immune system (promotes efficient antigen presentation and act as DAMP) specifically against the tumor and leads to tumor regression. This immunisation is not functional against a different tumour. It was used in autologous manner in clinical studies for gp96 and hsp70, but in vitro this works for all immune-relevant HSPs.[30][29]

Anticancer therapeutics

Intracellular heat shock proteins are highly expressed in cancerous cells and are essential to the survival of these cell types due to presence of mutated and over-expressed oncogenes.[31] Many HSPs can also promote invasiveness and metastasis formation in tumours, block apoptosis, or promote resistance to anti-cancer drugs.[54][32] Hence small molecule inhibitors of HSPs, especially Hsp90 show promise as anticancer agents.[55] The potent Hsp90 inhibitor 17-AAG was in clinical trials for the treatment of several types of cancer, but for various reasons unrelated to efficacy did not go on to Phase 3.[56][57] HSPgp96 also shows promise as an anticancer treatment and is currently in clinical trials against non-small cell lung cancer.[58]

Autoimmunity treatment

Acting as DAMPs, HSPs can extracellularly promote autoimmune reactions leading to diseases as rheumatoid arthritis or systemic lupus erythematosus.[29] Nevertheless, it was found, that application of some HSPs into patients is able to induce immune tolerance and treat autoimmune diseases. The underlying mechanism is not known. HSPs (especially hsp60 and hsp70) are used in clinical studies to treat rheumatoid arthritis and type I. diabetes.[35] Current therapeutic research areas in the treatment for DM include: long-term physical exercise, hot tub therapy (HTT), and alfalfa-derived HSP70 (aHSP70).[59]

Hsp90 inhibitors are another possible treatment for autoimmunity, because hsp90 is necessary for proper folding of many pro-inflammatory proteins (components of PI3K, MAPK and NF-kB cascades).[31]

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.[60]

Classification

The principal heat-shock proteins that have chaperone activity belong to five conserved classes: HSP33, HSP60, HSP70/HSP110, HSP90, HSP100, and the small heat-shock proteins (sHSPs).[11] A standard nomenclature for human HSP genes is available.[61]

Approximate molecular weight

(kDa)

Prokaryotic proteins Eukaryotic proteins Function
10 kDa GroES Hsp10 (HSPD) Co-factor of Hsp60
20–30 kDa GrpE In humans: GRPE1, GRPE2 Co-factor of DnaK/Hsp70, only for bacterial or mitochondrial/chloroplastic forms
20-30 kDa Hsp20 Human HSPB genes. Eleven members in mammals including Hsp27, HSPB6 or HspB1[61] Chaperones
40 kDa DnaJ Hsp40 (DNAJ*; three subfamilies in humans) Co-factor of Hsp70
60 kDa GroEL, 60kDa antigen Hsp60 (HSPE) Involved in protein folding after its post-translational import to the mitochondrion/chloroplast; a chaperonin
70 kDa DnaK Human HSPA genes. Includes Hsp71 (HSPA8), Hsp72 (HSPA1A), Grp78 (BiP, HSPA5); Hsx70 (HSPA1B) found only in primates.

Hsp110 genes are derived from this superfamily and are coded HSPH1 through 4.[61]

Protein folding and unfolding. Provides thermotolerance to cell on exposure to heat stress and protects against H2O2.[62] Also prevents protein folding during post-translational import into the mitochondria/chloroplast. Hsp110 provides tolerance of extreme temperature.
90 kDa HtpG, C62.5 Human HSPC genes. Includes Hsp90, Grp94 (HSPC4) Maintenance of steroid receptors and transcription factors
100 kDa ClpB, ClpA, ClpX Hsp104 (CLPB) Unfolding of insoluble protein aggregates; co-factor of DnaK/Hsp70

Although the most important members of each family are tabulated here, some species may express additional chaperones, co-chaperones, and heat shock proteins not listed. In addition, many of these proteins may have multiple splice variants (Hsp90α and Hsp90β, for instance) or conflicts of nomenclature (Hsp72 is sometimes called Hsp70).

See also

References

  1. ^ a b Ritossa F (1962). "A new puffing pattern induced by temperature shock and DNP in drosophila". Experimental. 18 (12): 571–573. doi:10.1007/BF02172188. ISSN 0014-4754. S2CID 32525462.
  2. ^ Matz JM, Blake MJ, Tatelman HM, Lavoi KP, Holbrook NJ (July 1995). "Characterization and regulation of cold-induced heat shock protein expression in mouse brown adipose tissue". The American Journal of Physiology. 269 (1 Pt 2): R38 – R47. doi:10.1152/ajpregu.1995.269.1.R38. PMID 7631901.
  3. ^ Cao Y, Ohwatari N, Matsumoto T, Kosaka M, Ohtsuru A, Yamashita S (August 1999). "TGF-beta1 mediates 70-kDa heat shock protein induction due to ultraviolet irradiation in human skin fibroblasts". Pflügers Archiv. 438 (3): 239–244. doi:10.1007/s004240050905. PMID 10398851. S2CID 28219505.
  4. ^ Laplante AF, Moulin V, Auger FA, Landry J, Li H, Morrow G, et al. (November 1998). "Expression of heat shock proteins in mouse skin during wound healing". The Journal of Histochemistry and Cytochemistry. 46 (11): 1291–1301. doi:10.1177/002215549804601109. PMID 9774628..
  5. ^ De Maio A (January 1999). "Heat shock proteins: facts, thoughts, and dreams". Shock. 11 (1): 1–12. doi:10.1097/00024382-199901000-00001. PMID 9921710.
  6. ^ Wu C (1995). "Heat shock transcription factors: structure and regulation". Annual Review of Cell and Developmental Biology. 11: 441–469. doi:10.1146/annurev.cb.11.110195.002301. PMID 8689565.
  7. ^ Li Z, Srivastava P (February 2004). Heat-shock proteins. Vol. Appendix 1. pp. Appendix 1T. doi:10.1002/0471142735.ima01ts58. ISBN 978-0471142737. PMID 18432918. S2CID 11858453. {{cite book}}: |journal= ignored (help)
  8. ^ Raboy B, Sharon G, Parag HA, Shochat Y, Kulka RG (1991). "Effect of stress on protein degradation: role of the ubiquitin system". Acta Biologica Hungarica. 42 (1–3): 3–20. PMID 1668897.
  9. ^ a b Lahvic JL, Ji Y, Marin P, Zuflacht JP, Springel MW, Wosen JE, et al. (December 2013). "Small heat shock proteins are necessary for heart migration and laterality determination in zebrafish". Developmental Biology. 384 (2): 166–180. doi:10.1016/j.ydbio.2013.10.009. PMC 3924900. PMID 24140541.
  10. ^ Ritossa F (June 1996). "Discovery of the heat shock response". Cell Stress & Chaperones. 1 (2): 97–98. doi:10.1379/1466-1268(1996)001<0097:dothsr>2.3.co;2 (inactive 1 November 2024). PMC 248460. PMID 9222594.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
  11. ^ a b Schlesinger MJ (July 1990). "Heat shock proteins". The Journal of Biological Chemistry. 265 (21): 12111–12114. doi:10.1016/S0021-9258(19)38314-0. PMID 2197269.
  12. ^ Tissières A, Mitchell HK, Tracy UM (April 1974). "Protein synthesis in salivary glands of Drosophila melanogaster: relation to chromosome puffs". Journal of Molecular Biology. 84 (3): 389–398. doi:10.1016/0022-2836(74)90447-1. PMID 4219221.
  13. ^ a b Marvin M, O'Rourke D, Kurihara T, Juliano CE, Harrison KL, Hutson LD (February 2008). "Developmental expression patterns of the zebrafish small heat shock proteins". Developmental Dynamics. 237 (2): 454–463. doi:10.1002/dvdy.21414. PMID 18161059. S2CID 25079120.
  14. ^ Santoro MG (January 2000). "Heat shock factors and the control of the stress response". Biochemical Pharmacology. 59 (1): 55–63. doi:10.1016/S0006-2952(99)00299-3. PMID 10605935.
  15. ^ Walsh NP, Alba BM, Bose B, Gross CA, Sauer RT (April 2003). "OMP peptide signals initiate the envelope-stress response by activating DegS protease via relief of inhibition mediated by its PDZ domain". Cell. 113 (1): 61–71. doi:10.1016/S0092-8674(03)00203-4. PMID 12679035. S2CID 11316659.
  16. ^ Narberhaus F (2010). "Translational control of bacterial heat shock and virulence genes by temperature-sensing mRNAs". RNA Biology. 7 (1): 84–89. doi:10.4161/rna.7.1.10501. PMID 20009504.
  17. ^ Petersen NS, Mitchell HK (March 1981). "Recovery of protein synthesis after heat shock: prior heat treatment affects the ability of cells to translate mRNA". Proceedings of the National Academy of Sciences of the United States of America. 78 (3): 1708–1711. Bibcode:1981PNAS...78.1708P. doi:10.1073/pnas.78.3.1708. PMC 319202. PMID 6785759.
  18. ^ a b Burton V, Mitchell HK, Young P, Petersen NS (August 1988). "Heat shock protection against cold stress of Drosophila melanogaster". Molecular and Cellular Biology. 8 (8): 3550–3552. doi:10.1128/mcb.8.8.3550. PMC 363594. PMID 3145413.
  19. ^ Walter S, Buchner J (April 2002). "Molecular chaperones--cellular machines for protein folding". Angewandte Chemie. 41 (7): 1098–1113. doi:10.1002/1521-3773(20020402)41:7<1098::AID-ANIE1098>3.0.CO;2-9. PMID 12491239. S2CID 8509592.
  20. ^ Borges JC, Ramos CH (April 2005). "Protein folding assisted by chaperones". Protein and Peptide Letters. 12 (3): 257–261. doi:10.2174/0929866053587165. PMID 15777275.
  21. ^ Mitchell HK, Petersen NS, Buzin CH (August 1985). "Self-degradation of heat shock proteins". Proceedings of the National Academy of Sciences of the United States of America. 82 (15): 4969–73. Bibcode:1985PNAS...82.4969M. doi:10.1073/pnas.82.15.4969. PMC 390479. PMID 3927294.
  22. ^ Benjamin IJ, McMillan DR (July 1998). "Stress (heat shock) proteins: molecular chaperones in cardiovascular biology and disease". Circulation Research. 83 (2): 117–132. doi:10.1161/01.res.83.2.117. PMID 9686751.
  23. ^ Antonova G, Lichtenbeld H, Xia T, Chatterjee A, Dimitropoulou C, Catravas JD (2007). "Functional significance of hsp90 complexes with NOS and sGC in endothelial cells". Clinical Hemorheology and Microcirculation. 37 (1–2): 19–35. PMID 17641392. Archived from the original on 2013-01-28.
  24. ^ Mai AS, Dos Santos AB, Beber LC, Basso RD, Sulzbacher LM, Goettems-Fiorin PB, et al. (2017-12-13). "Exercise Training under Exposure to Low Levels of Fine Particulate Matter: Effects on Heart Oxidative Stress and Extra-to-Intracellular HSP70 Ratio". Oxidative Medicine and Cellular Longevity. 2017: 9067875. doi:10.1155/2017/9067875. PMC 5745714. PMID 29387296.
  25. ^ Rosenfeld GE, Mercer EJ, Mason CE, Evans T (September 2013). "Small heat shock proteins Hspb7 and Hspb12 regulate early steps of cardiac morphogenesis". Developmental Biology. 381 (2): 389–400. doi:10.1016/j.ydbio.2013.06.025. PMC 3777613. PMID 23850773.
  26. ^ McLemore EC, Tessier DJ, Thresher J, Komalavilas P, Brophy CM (July 2005). "Role of the small heat shock proteins in regulating vascular smooth muscle tone". Journal of the American College of Surgeons. 201 (1): 30–36. doi:10.1016/j.jamcollsurg.2005.03.017. PMID 15978441.
  27. ^ Fan GC, Ren X, Qian J, Yuan Q, Nicolaou P, Wang Y, et al. (April 2005). "Novel cardioprotective role of a small heat-shock protein, Hsp20, against ischemia/reperfusion injury". Circulation. 111 (14): 1792–1799. doi:10.1161/01.CIR.0000160851.41872.C6. PMID 15809372.
  28. ^ Salinthone S, Tyagi M, Gerthoffer WT (July 2008). "Small heat shock proteins in smooth muscle". Pharmacology & Therapeutics. 119 (1): 44–54. doi:10.1016/j.pharmthera.2008.04.005. PMC 2581864. PMID 18579210.
  29. ^ a b c d e f g h i j k l m n Binder RJ (December 2014). "Functions of heat shock proteins in pathways of the innate and adaptive immune system". Journal of Immunology. 193 (12): 5765–5771. doi:10.4049/jimmunol.1401417. PMC 4304677. PMID 25480955.
  30. ^ a b c d e f g h i j k l m n o Murshid A, Gong J, Calderwood SK (2012). "The role of heat shock proteins in antigen cross presentation". Frontiers in Immunology. 3: 63. doi:10.3389/fimmu.2012.00063. PMC 3342350. PMID 22566944.
  31. ^ a b c Tukaj S, Węgrzyn G (March 2016). "Anti-Hsp90 therapy in autoimmune and inflammatory diseases: a review of preclinical studies". Cell Stress & Chaperones. 21 (2): 213–218. doi:10.1007/s12192-016-0670-z. PMC 4786535. PMID 26786410.
  32. ^ a b c d e Graner MW (2016). "HSP90 and Immune Modulation in Cancer". Hsp90 in Cancer: Beyond the Usual Suspects. Advances in Cancer Research. Vol. 129. Elsevier. pp. 191–224. doi:10.1016/bs.acr.2015.10.001. ISBN 9780128022900. PMID 26916006.
  33. ^ a b c d e Deffit SN, Blum JS (December 2015). "A central role for HSC70 in regulating antigen trafficking and MHC class II presentation". Molecular Immunology. 68 (2 Pt A): 85–88. doi:10.1016/j.molimm.2015.04.007. PMC 4623969. PMID 25953005.
  34. ^ Linder, Manuel; Pogge von Strandmann, Elke (January 2021). "The Role of Extracellular HSP70 in the Function of Tumor-Associated Immune Cells". Cancers. 13 (18): 4721. doi:10.3390/cancers13184721. ISSN 2072-6694. PMC 8466959. PMID 34572948.
  35. ^ a b Jansen MA, Spiering R, Broere F, van Laar JM, Isaacs JD, van Eden W, Hilkens CM (January 2018). "Targeting of tolerogenic dendritic cells towards heat-shock proteins: a novel therapeutic strategy for autoimmune diseases?". Immunology. 153 (1): 51–59. doi:10.1111/imm.12811. PMC 5721256. PMID 28804903.
  36. ^ Xu D, Zalmas LP, La Thangue NB (July 2008). "A transcription cofactor required for the heat-shock response". EMBO Reports. 9 (7): 662–669. doi:10.1038/embor.2008.70. PMC 2475325. PMID 18451878.
  37. ^ Salamanca HH, Fuda N, Shi H, Lis JT (August 2011). "An RNA aptamer perturbs heat shock transcription factor activity in Drosophila melanogaster". Nucleic Acids Research. 39 (15): 6729–6740. doi:10.1093/nar/gkr206. PMC 3159435. PMID 21576228.
  38. ^ Dai C, Whitesell L, Rogers AB, Lindquist S (September 2007). "Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis". Cell. 130 (6): 1005–1018. doi:10.1016/j.cell.2007.07.020. PMC 2586609. PMID 17889646.
  39. ^ Salamanca HH, Antonyak MA, Cerione RA, Shi H, Lis JT (2014). "Inhibiting heat shock factor 1 in human cancer cells with a potent RNA aptamer". PLOS ONE. 9 (5): e96330. Bibcode:2014PLoSO...996330S. doi:10.1371/journal.pone.0096330. PMC 4011729. PMID 24800749.
  40. ^ Alam, Uazman; Asghar, Omar; Azmi, Shazli; Malik, Rayaz A. (2014-01-01), Zochodne, Douglas W.; Malik, Rayaz A. (eds.), "Chapter 15 - General aspects of diabetes mellitus", Handbook of Clinical Neurology, Diabetes and the Nervous System, 126, Elsevier: 211–222, doi:10.1016/B978-0-444-53480-4.00015-1, ISBN 9780444534804, PMID 25410224, retrieved 2022-08-30
  41. ^ Krause M, Heck TG, Bittencourt A, Scomazzon SP, Newsholme P, Curi R, Homem de Bittencourt PI (2015-02-26). "The chaperone balance hypothesis: the importance of the extracellular to intracellular HSP70 ratio to inflammation-driven type 2 diabetes, the effect of exercise, and the implications for clinical management". Mediators of Inflammation. 2015: 249205. doi:10.1155/2015/249205. PMC 4357135. PMID 25814786.
  42. ^ Birk OS, Douek DC, Elias D, Takacs K, Dewchand H, Gur SL, et al. (February 1996). "A role of Hsp60 in autoimmune diabetes: analysis in a transgenic model". Proceedings of the National Academy of Sciences of the United States of America. 93 (3): 1032–1037. Bibcode:1996PNAS...93.1032B. doi:10.1073/pnas.93.3.1032. PMC 40025. PMID 8577709.
  43. ^ Seibert P, Anklam CF, Costa-Beber LC, Sulzbacher LM, Sulzbacher MM, Sangiovo AM, et al. (June 2022). "Increased eHSP70-to-iHSP70 ratio in prediabetic and diabetic postmenopausal women: a biomarker of cardiometabolic risk". Cell Stress & Chaperones. 27 (5): 523–534. doi:10.1007/s12192-022-01288-8. PMC 9485348. PMID 35767179. S2CID 250114357.
  44. ^ Nakhjavani M, Morteza A, Khajeali L, Esteghamati A, Khalilzadeh O, Asgarani F, Outeiro TF (November 2010). "Increased serum HSP70 levels are associated with the duration of diabetes". Cell Stress & Chaperones. 15 (6): 959–964. doi:10.1007/s12192-010-0204-z. PMC 3024058. PMID 20496051.
  45. ^ Albakova, Zarema; Siam, Mohammad Kawsar Sharif; Sacitharan, Pradeep Kumar; Ziganshin, Rustam H.; Ryazantsev, Dmitriy Y.; Sapozhnikov, Alexander M. (2021-02-01). "Extracellular heat shock proteins and cancer: New perspectives". Translational Oncology. 14 (2): 100995. doi:10.1016/j.tranon.2020.100995. ISSN 1936-5233. PMC 7749402. PMID 33338880. S2CID 229324108.
  46. ^ Lu, Wei; Wang, Yongwu; Gan, Min; Duan, Qingyun (2021-01-22). "Prognosis and predictive value of heat-shock proteins expression in oral cancer: A PRISMA-compliant meta-analysis". Medicine. 100 (3): e24274. doi:10.1097/MD.0000000000024274. PMC 7837937. PMID 33546049.
  47. ^ Staroverov, Sergey A.; Kozlov, Sergey V.; Brovko, Fedor A.; Fursova, Ksenia K.; Shardin, Vitaly V.; Fomin, Alexander S.; Gabalov, Konstantin P.; Soldatov, Dmitry A.; Zhnichkova, Elena G.; Dykman, Lev A.; Guliy, Olga I. (2022-09-01). "Phage antibodies against heat shock proteins as tools for in vitro cancer diagnosis". Biosensors and Bioelectronics: X. 11: 100211. doi:10.1016/j.biosx.2022.100211. ISSN 2590-1370. S2CID 251559265.
  48. ^ Yildiz, Mehmet Taha; Tutar, Lütfi; Giritlioğlu, Nazlı Irmak; Bayram, Banu; Tutar, Yusuf (2022), Allmer, Jens; Yousef, Malik (eds.), "MicroRNAs and Heat Shock Proteins in Breast Cancer Biology", miRNomics: MicroRNA Biology and Computational Analysis, Methods in Molecular Biology, vol. 2257, New York, NY: Springer US, pp. 293–310, doi:10.1007/978-1-0716-1170-8_15, ISBN 978-1-0716-1170-8, PMID 34432285, S2CID 237291365, retrieved 2022-09-11
  49. ^ a b Nishikawa M, Takemoto S, Takakura Y (April 2008). "Heat shock protein derivatives for delivery of antigens to antigen presenting cells". International Journal of Pharmaceutics. 354 (1–2): 23–27. doi:10.1016/j.ijpharm.2007.09.030. PMID 17980980.
  50. ^ Bendz H, Ruhland SC, Pandya MJ, Hainzl O, Riegelsberger S, Braüchle C, et al. (October 2007). "Human heat shock protein 70 enhances tumor antigen presentation through complex formation and intracellular antigen delivery without innate immune signaling". The Journal of Biological Chemistry. 282 (43): 31688–31702. doi:10.1074/jbc.M704129200. PMID 17684010.
  51. ^ Anand, Geeta (2 August 2007). "Cancer Drug Fails, So Maker Tries New Pitch". The Wall Street Journal. Retrieved 10 April 2018.
  52. ^ Sedlacek, Abigail L.; Kinner-Bibeau, Lauren B.; Wang, Yifei; Mizes, Alicia P.; Binder, Robert J. (2021-08-09). "Tunable heat shock protein-mediated NK cell responses are orchestrated by STAT1 in Antigen Presenting Cells". Scientific Reports. 11 (1): 16106. Bibcode:2021NatSR..1116106S. doi:10.1038/s41598-021-95578-3. ISSN 2045-2322. PMC 8352880. PMID 34373574.
  53. ^ Binder RJ (April 2008). "Heat-shock protein-based vaccines for cancer and infectious disease". Expert Review of Vaccines. 7 (3): 383–393. doi:10.1586/14760584.7.3.383. PMID 18393608. S2CID 42072204.
  54. ^ Wu J, Liu T, Rios Z, Mei Q, Lin X, Cao S (March 2017). "Heat Shock Proteins and Cancer". Trends in Pharmacological Sciences. 38 (3): 226–256. doi:10.1016/j.tips.2016.11.009. PMID 28012700.
  55. ^ Didelot C, Lanneau D, Brunet M, Joly AL, De Thonel A, Chiosis G, Garrido C (2007). "Anti-cancer therapeutic approaches based on intracellular and extracellular heat shock proteins". Current Medicinal Chemistry. 14 (27): 2839–2847. doi:10.2174/092986707782360079. PMID 18045130.
  56. ^ Solit DB, Rosen N (2006). "Hsp90: a novel target for cancer therapy". Current Topics in Medicinal Chemistry. 6 (11): 1205–1214. doi:10.2174/156802606777812068. PMID 16842157.
  57. ^ The Myeloma Beacon Staff (22 July 2010). "Bristol-Myers Squibb Halts Development of Tanespimycin". The Myeloma Beacon. Archived from the original on 9 January 2018. Retrieved 9 January 2018.
  58. ^ Clinical trial number NCT01504542 for "Immune Response and Safety of HS110 Vaccine in Combination With Erlotinib in Patients With Non-Small Cell Lung Cancer" at ClinicalTrials.gov
  59. ^ Mulyani WR, Sanjiwani MI, Prabawa IP, Lestari AA, Wihandani DM, Suastika K, et al. (2020). "Chaperone-Based Therapeutic Target Innovation: Heat Shock Protein 70 (HSP70) for Type 2 Diabetes Mellitus". Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 13: 559–568. doi:10.2147/DMSO.S232133. PMC 7051252. PMID 32161482.
  60. ^ Vinocur B, Altman A (April 2005). "Recent advances in engineering plant tolerance to abiotic stress: achievements and limitations". Current Opinion in Biotechnology. 16 (2): 123–132. doi:10.1016/j.copbio.2005.02.001. PMID 15831376.
  61. ^ a b c Kampinga HH, Hageman J, Vos MJ, Kubota H, Tanguay RM, Bruford EA, et al. (January 2009). "Guidelines for the nomenclature of the human heat shock proteins". Cell Stress & Chaperones. 14 (1): 105–111. doi:10.1007/s12192-008-0068-7. PMC 2673902. PMID 18663603.
  62. ^ Delaney JM (October 1990). "Requirement of the Escherichia coli dnaK gene for thermotolerance and protection against H2O2". Journal of General Microbiology. 136 (10): 2113–8. doi:10.1099/00221287-136-10-2113. PMID 2269877.
Wikimedia Commons has media related to Heat-shock proteins.