Emerging role of heat shock proteins in biology and medicine.

All cells, procaryotic and eucaryotic, respond to an elevation in temperature by increasing the synthesis of a family of proteins collectively known as heat shock proteins (HSPs). HSPs are among the most highly conserved and abundant proteins in nature. Studies on the regulation of the synthesis of HSPs have for several years shed light on the mechanisms regulating gene expression. The results from recent years, showing that HSPs play crucial roles in a wide variety of normal cellular processes, has made them an object of even broader interest, first to molecular and cellular biologists and later to specialists in various fields of medicine including oncology, immunology, infectious disease, autoimmunity, embryology, neurology and endocrinology. The aim of this review is to briefly summarize our present knowledge of the regulation of the heat shock response and the structure of the relevant gene products, HSPs. Moreover, some of the exciting associations between HSPs and various fields of medicine will be discussed.

[1]  S. Pierce,et al.  Heat Shock Proteins and Antigen Processing and Presentation , 1991 .

[2]  M. Jäättelä Biologic activities and mechanisms of action of tumor necrosis factor-alpha/cachectin. , 1991, Laboratory investigation; a journal of technical methods and pathology.

[3]  Peter K. Sorger,et al.  Heat shock factor is regulated differently in yeast and HeLa cells , 1987, Nature.

[4]  J. Brugge,et al.  Interaction between the Rous sarcoma virus transforming protein and two cellular phosphoproteins: analysis of the turnover and distribution of this complex , 1983, Molecular and cellular biology.

[5]  U. Bond,et al.  The chicken ubiquitin gene contains a heat shock promoter and expresses an unstable mRNA in heat-shocked cells , 1986, Molecular and cellular biology.

[6]  M. Jäättelä,et al.  Heat shock protects WEHI‐164 target cells from the cytolysis by tumor necrosis factors α and β , 1989 .

[7]  H. Pelham Speculations on the functions of the major heat shock and glucose-regulated proteins , 1986, Cell.

[8]  W. Welch,et al.  Interaction of Hsp 70 with newly synthesized proteins: implications for protein folding and assembly. , 1990, Science.

[9]  Winfield Jb,et al.  Stress proteins, autoimmunity, and autoimmune disease , 1991 .

[10]  R. Kingston,et al.  Heat-inducible human factor that binds to a human hsp70 promoter , 1987, Molecular and cellular biology.

[11]  R. Kingston,et al.  Isolation of a cDNA for HSF2: evidence for two heat shock factor genes in humans. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[12]  I. Dunham,et al.  Human major histocompatibility complex contains genes for the major heat shock protein HSP70. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[13]  G. Evan,et al.  Nuclear colocalization of cellular and viral myc proteins with HSP70 in myc-overexpressing cells , 1991, Journal of virology.

[14]  C. Benz,et al.  Stress response protein (srp-27) determination in primary human breast carcinomas: clinical, histologic, and prognostic correlations. , 1991, Journal of the National Cancer Institute.

[15]  G. Bahr,et al.  HLA-DR-associated isotype-specific regulation of antibody levels to mycobacteria in rheumatoid arthritis. , 1988, Clinical and experimental immunology.

[16]  J. Garrels,et al.  Biochemical characterization of the mammalian stress proteins and identification of two stress proteins as glucose- and Ca2+-ionophore-regulated proteins. , 1983, The Journal of biological chemistry.

[17]  J. Brugge,et al.  The specific interaction of the Rous sarcoma virus transforming protein, pp60src, with two cellular proteins , 1981, Cell.

[18]  R. Morimoto,et al.  Mutational analysis of the human HSP70 protein: distinct domains for nucleolar localization and adenosine triphosphate binding , 1989, The Journal of cell biology.

[19]  P. Schiller,et al.  Isolation and functional analysis of a human 70,000-dalton heat shock protein gene segment. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[20]  A. Scherf,et al.  A heat shock‐like protein from the human malaria parasite plasmodium falciparum induces autoantibodies , 1989, European journal of immunology.

[21]  G. Hahn,et al.  Glucocorticoid‐induced heat resistance in mammalian cells , 1986, Journal of cellular physiology.

[22]  D. Edwards,et al.  Distribution of an estrogen-induced protein with a molecular weight of 24,000 in normal and malignant human tissues and cells. , 1983, Cancer research.

[23]  S. R. Terlecky,et al.  A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins. , 1989, Science.

[24]  G. Khoury,et al.  p53 transformation-related protein: detection by monoclonal antibody in mouse and human cells. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[25]  S. Rabindran,et al.  Molecular cloning and expression of a human heat shock factor, HSF1. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[26]  K. Scharf,et al.  Three tomato genes code for heat stress transcription factors with a region of remarkable homology to the DNA‐binding domain of the yeast HSF. , 1990, The EMBO journal.

[27]  C. Hunt,et al.  Identification and sequence analysis of a new member of the mouse HSP70 gene family and characterization of its unique cellular and developmental pattern of expression in the male germ line , 1988, Molecular and cellular biology.

[28]  L. Aujame,et al.  The major inducible heat shock protein hsp68 is not required for acquisition of thermal resistance in mouse plasmacytoma cell lines , 1988, Molecular and cellular biology.

[29]  A. Levine,et al.  Mutation is required to activate the p53 gene for cooperation with the ras oncogene and transformation , 1989, Journal of virology.

[30]  R. Morimoto,et al.  Expression of human HSP70 during the synthetic phase of the cell cycle. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[31]  L. Hightower,et al.  Induction of a chicken small heat shock (stress) protein: evidence of multilevel posttranscriptional regulation , 1990, Molecular and cellular biology.

[32]  C. S. Parker,et al.  Isolation of the gene encoding the S. cerevisiae heat shock transcription factor , 1988, Cell.

[33]  D. Edwards,et al.  Detection of a Mr 24,000 estrogen-regulated protein in human breast cancer by monoclonal antibodies. , 1983, Cancer research.

[34]  M. Meselson,et al.  Accumulation of a specific subset of D. melanogaster heat shock mRNAs in normal development without heat shock , 1983, Cell.

[35]  R. Tjian,et al.  Two transcriptional activators, CCAAT-box-binding transcription factor and heat shock transcription factor, interact with a human hsp70 gene promoter , 1987, Molecular and cellular biology.

[36]  S. Kaufmann,et al.  Heat shock proteins and the immune response. , 1990, Immunology today.

[37]  S. Lindquist,et al.  The heat-shock proteins. , 1988, Annual review of genetics.

[38]  p53 mutations, ras mutations, and p53-heat shock 70 protein complexes in human lung carcinoma cell lines. , 1991, Cancer research.

[39]  H. Pelham Hsp70 accelerates the recovery of nucleolar morphology after heat shock. , 1984, The EMBO journal.

[40]  G. Li,et al.  Thermal response of rat fibroblasts stably transfected with the human 70-kDa heat shock protein-encoding gene. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[41]  G. Lorimer,et al.  Identification of a groES-like chaperonin in mitochondria that facilitates protein folding. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[42]  J. Winfield,et al.  Brief Definitive Report AUTOANTIBODIES TO THE CONSTITUTIVE 73-kD MEMBER OF THE hsp70 FAMILY OF HEAT SHOCK PROTEINS IN SYSTEMIC LUPUS ERYTHEMATOSUS , 2022 .

[43]  I. Cohen,et al.  Autoimmunity, microbial immunity and the immunological homunculus. , 1991, Immunology today.

[44]  H. Pelham A regulatory upstream promoter element in the Drosophila Hsp 70 heat-shock gene , 1982, Cell.

[45]  C. McLaughlin,et al.  Induction of heat shock proteins and thermotolerance by ethanol in Saccharomycescerevisiae , 1982 .

[46]  L. Klareskog,et al.  Presence of Human 65 kD Heat Shock Protein (hsp) in Inflamed Joints and Subcutaneous Nodules of RA Patients , 1990, Scandinavian journal of immunology.

[47]  W. McGuire,et al.  Induction of the estrogen-regulated "24K" protein by heat shock. , 1989, Cancer research.

[48]  P. Chrétien,et al.  Enhanced constitutive expression of the 27‐kDa heat shock proteins in heat‐resistant variants from chinese hamster cells , 1988, Journal of cellular physiology.

[49]  M. Bienz A CCAAT box confers cell-type-specific regulation on the Xenopus hsp70 gene in oocytes , 1986, Cell.

[50]  A. Zantema,et al.  The expression of heat shock protein hsp27 and a complexed 22-kilodalton protein is inversely correlated with oncogenicity of adenovirus-transformed cells , 1989, Journal of virology.

[51]  E. Craig,et al.  Eukaryotic Mr 83,000 heat shock protein has a homologue in Escherichia coli. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[52]  G. Li,et al.  Heat-resistant variants of Chinese hamster fibroblasts altered in expression of heat shock protein. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[53]  R. Morimoto,et al.  Conserved features of eukaryotic hsp70 genes revealed by comparison with the nucleotide sequence of human hsp70. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[54]  E. Delwart,et al.  Regulation of heat‐shock genes: a DNA sequence upstream of Drosophila hsp70 genes is essential for their induction in monkey cells. , 1982, The EMBO journal.

[55]  M. Morange,et al.  Spontaneous high expression of heat‐shock proteins in mouse embryonal carcinoma cells and ectoderm from day 8 mouse embryo. , 1983, The EMBO journal.

[56]  A. Fornace,et al.  Induction of heat shock protein transcripts and B2 transcripts by various stresses in Chinese hamster cells. , 1989, Experimental cell research.

[57]  W. Welch,et al.  Characterization and purification of the small 28,000-dalton mammalian heat shock protein. , 1987, The Journal of biological chemistry.

[58]  K. Riabowol,et al.  Heat shock is lethal to fibroblasts microinjected with antibodies against hsp70. , 1988, Science.

[59]  E. Margoliash,et al.  Identification of a peptide binding protein that plays a role in antigen presentation. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[60]  C. Janeway,et al.  Elevated temperature regulates tumor necrosis factor‐mediated immune killing , 1989, European journal of immunology.

[61]  J. Nevins Induction of the synthesis of a 70,000 dalton mammalian heat shock protein by the adenovirus E1A gene product , 1982, Cell.

[62]  R. Morimoto,et al.  Posttranscriptional regulation of hsp70 expression in human cells: effects of heat shock, inhibition of protein synthesis, and adenovirus infection on translation and mRNA stability , 1987, Molecular and cellular biology.

[63]  C. Kahn,et al.  The 90-kDa heat shock protein (hsp-90) possesses an ATP binding site and autophosphorylating activity. , 1991, The Journal of biological chemistry.

[64]  A. Levine,et al.  Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life , 1988, Molecular and cellular biology.

[65]  R. Weinberg,et al.  An interaction between p21ras and heat shock protein hsp60, a chaperonin. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[66]  R. Young,et al.  Immune Recognition of Stress Proteins in Infection and in Surveillance of Stressed Cells , 1991 .

[67]  R. Morimoto,et al.  Cloning and characterization of two mouse heat shock factors with distinct inducible and constitutive DNA-binding ability. , 1991, Genes & development.

[68]  P. Sorger,et al.  Yeast heat shock factor is an essential DNA-binding protein that exhibits temperature-dependent phosphorylation , 1988, Cell.

[69]  G. Stein,et al.  Sequence and organization of genes encoding the human 27 kDa heat shock protein. , 1986, Nucleic acids research.

[70]  A. Levine,et al.  Characterization of a 54K Dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells , 1979, Cell.

[71]  C. Harley,et al.  Primary structure of a human mitochondrial protein homologous to the bacterial and plant chaperonins and to the 65-kilodalton mycobacterial antigen , 1989, Molecular and cellular biology.

[72]  J. Ellis Proteins as molecular chaperones , 1987, Nature.

[73]  F. Hartl,et al.  Protein folding in mitochondria requires complex formation with hsp60 and ATP hydrolysis , 1989, Nature.

[74]  Carl Wu,et al.  Stress-induced oligomerization and chromosomal relocalization of heat-shock factor , 1991, Nature.

[75]  W. Welch Phorbol ester, calcium ionophore, or serum added to quiescent rat embryo fibroblast cells all result in the elevated phosphorylation of two 28,000-dalton mammalian stress proteins. , 1985, The Journal of biological chemistry.

[76]  C. Georgopoulos,et al.  9 Properties of the Escherichia coli Heat Shock Proteins and Their Role in Bacteriophage λ Growth , 1990 .

[77]  E. Gerner,et al.  Dissociation of 68,000 Mr heat shock protein synthesis from thermotolerance expression in rat fibroblasts. , 1984, Radiation research.

[78]  J. Amin,et al.  Key features of heat shock regulatory elements , 1988, Molecular and cellular biology.

[79]  A. Levine,et al.  Immunological evidence for the association of p53 with a heat shock protein, hsc70, in p53-plus-ras-transformed cell lines , 1987, Molecular and cellular biology.

[80]  R. Johnston,et al.  Competitive inhibition of hsp70 gene expression causes thermosensitivity. , 1988, Science.

[81]  G. Li,et al.  Heat shock protein hsp70 protects cells from thermal stress even after deletion of its ATP-binding domain. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[82]  J. Rothman,et al.  Peptide binding and release by proteins implicated as catalysts of protein assembly. , 1989, Science.

[83]  J. Jenkins,et al.  Characterization of mutant p53-hsp72/73 protein-protein complexes by transient expression in monkey COS cells , 1988, Molecular and cellular biology.

[84]  D. Pauli,et al.  Characterization of HSP27 and three immunologically related polypeptides during Drosophila development. , 1988, Experimental cell research.

[85]  J. M. Velazquez,et al.  hsp70: Nuclear concentration during environmental stress and cytoplasmic storage during recovery , 1984, Cell.

[86]  R L Kassel,et al.  An endotoxin-induced serum factor that causes necrosis of tumors. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[87]  D. Lowe,et al.  Proteins related to the mouse L-cell major heat shock protein are synthesized in the absence of heat shock gene expression. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[88]  W. Welch,et al.  Nuclear and nucleolar localization of the 72,000-dalton heat shock protein in heat-shocked mammalian cells. , 1984, The Journal of biological chemistry.

[89]  E. Berger,et al.  Synthesis of low molecular weight heat shock peptides stimulated by ecdysterone in a cultured Drosophila cell line. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[90]  W. Neupert,et al.  Heat shock proteins hsp60 and hsp70: their roles in folding, assembly and membrane translocation of proteins. , 1991, Current topics in microbiology and immunology.

[91]  Peter K. Sorger,et al.  Heat shock factor and the heat shock response , 1991, Cell.

[92]  R. Morimoto,et al.  Mitogen and lymphokine stimulation of heat shock proteins in T lymphocytes. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[93]  J. Landry,et al.  Heat shock resistance conferred by expression of the human HSP27 gene in rodent cells , 1989, The Journal of cell biology.

[94]  A. Levine,et al.  The p53 proto-oncogene can act as a suppressor of transformation , 1989, Cell.

[95]  K. Yamada,et al.  HSP47: a tissue-specific, transformation-sensitive, collagen-binding heat shock protein of chicken embryo fibroblasts , 1991, Molecular and cellular biology.

[96]  S. Krane,et al.  Hormone 1 alpha,25-dihydroxyvitamin D3 modulates heat shock response in monocytes. , 1987, The American journal of physiology.

[97]  W. Welch,et al.  Medium tumor antigen of polyomavirus transformation-defective mutant NG59 is associated with 73-kilodalton heat shock protein , 1987, Journal of virology.

[98]  Carl Wu An exonuclease protection assay reveals heat-shock element and TATA box DNA-binding proteins in crude nuclear extracts , 1985, Nature.

[99]  H. Pelham,et al.  Activation of the Drosophila hsp27 promoter by heat shock and by ecdysone involves independent and remote regulatory sequences , 1986, The EMBO journal.

[100]  R. Hallberg,et al.  A highly evolutionarily conserved mitochondrial protein is structurally related to the protein encoded by the Escherichia coli groEL gene , 1988, Molecular and Cellular Biology.

[101]  Carl Wu,et al.  Molecular cloning and expression of a hexameric Drosophila heat shock factor subject to negative regulation , 1990, Cell.

[102]  G. Zupi,et al.  Heat‐shock proteins produced by two human melanoma cell lines: Absence of correlation with thermosensitivity , 1984, International journal of cancer.

[103]  G. Kramer,et al.  The 90-kilodalton peptide of the heme-regulated eIF-2 alpha kinase has sequence similarity with the 90-kilodalton heat shock protein. , 1987, Biochemistry.

[104]  M. Bienz Developmental control of the heat shock response in Xenopus. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[105]  R. Morimoto,et al.  Cell cycle-dependent association of HSP70 with specific cellular proteins , 1989, The Journal of cell biology.

[106]  H. Pelham,et al.  Heat shock and the sorting of luminal ER proteins. , 1989, The EMBO journal.

[107]  Gloria C. Li Induction of thermotolerance and enhanced heat shock protein synthesis in chinese hamster fibroblasts by sodium arsenite and by ethanol , 1983, Journal of cellular physiology.

[108]  R. Young,et al.  Stress proteins and immunology. , 1990, Annual review of immunology.

[109]  I. Cohen,et al.  Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[110]  I. Benjamin,et al.  Activation of the heat shock transcription factor by hypoxia in mammalian cells. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[111]  F. Breedveld,et al.  SYNOVIAL FLUID T CELL REACTIVITY AGAINST 65 kD HEAT SHOCK PROTEIN OF MYCOBACTERIA IN EARLY CHRONIC ARTHRITIS , 1988, The Lancet.

[112]  Burns Cp,et al.  Influence of rate of heating on thermosensitivity of L1210 leukemia: membrane lipids and Mr 70,000 heat shock protein , 1986 .

[113]  Carl Wu,et al.  Induction of sequence-specific binding of Drosophila heat shock activator protein without protein synthesis , 1987, Nature.

[114]  R. Morimoto,et al.  Detection of three protein binding sites in the serum-regulated promoter of the human gene encoding the 70-kDa heat shock protein. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[115]  Peter K. Sorger,et al.  Yeast heat shock factor contains separable transient and sustained response transcriptional activators , 1990, Cell.

[116]  W. McGuire,et al.  Chromosomal assignments of human 27-kDa heat shock protein gene family , 1989, Somatic cell and molecular genetics.

[117]  J. Subjeck,et al.  Induction of glucose-regulated proteins during anaerobic exposure and of heat-shock proteins after reoxygenation. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[118]  A. Levine,et al.  The p53 tumour suppressor gene , 1991, Nature.

[119]  B. Polla,,et al.  Erythrophagocytosis induces heat shock protein synthesis by human monocytes-macrophages. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[120]  R. Morimoto,et al.  Transcription of the human hsp70 gene is induced by serum stimulation. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[121]  Z. Werb,et al.  Correlation between synthesis of heat shock proteins and development of thermotolerance in Chinese hamster fibroblasts. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[122]  T. Creighton Unfolding protein folding , 1991, Nature.

[123]  F. Hartl,et al.  Role of HSP60 in Folding/Assembly of Mitochondrial Proteins , 1991 .

[124]  R. Kingston,et al.  Human HSP70 promoter contains at least two distinct regulatory domains. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[125]  N. Marceau,et al.  Synthesis and degradation of heat shock proteins during development and decay of thermotolerance. , 1982, Cancer research.

[126]  M. Jäättelä,et al.  Major heat shock protein hsp70 protects tumor cells from tumor necrosis factor cytotoxicity. , 1992, The EMBO journal.