AN INTRODUCTION TO STRESS PROTEINS

The general response to stress

             The response to stress has been documented in many different biological systems [1].  A common feature of this response is the induction (increased synthesis) of a group of proteins which were first termed heat shock proteins due to their initial discovery in cells exposed to hyperthermia (elevated temperatures) [2].  An entire family of these proteins, now also more generally known as stress proteins, has since been identified [3].   Ranging in size from approximately 15kDa to 110kDa in molecular weight, some of these proteins are constitutive (are found in the cell under normal conditions), while others have been found to be induced in response to a variety of cellular stresses including heavy metals [4], oxidative stress [5], and ischemia [6] (for general reviews, see [7]; [8]).  Why does the cell make these proteins?  In fact, this seems to be an adaptive response, as the presence of  stress proteins has been shown to confer resistance to further stresses such as additional hyperthermia [9].

            The mechanism of how induction occurs in eukaryotes is relatively well understood and involves binding of an activated heat shock factor protein (HSF) to a responsive heat shock element (HSE) in the genome  [3], which initiates the processes of transcription and translation for these proteins.  There is some evidence that protein kinases A (PKA) and C (PKC) may also play a role in regulation of promoter activity, as the binding of HSF to DNA in a glioblastoma cell line was suppressed by PKC and PKA inhibitors and the accumulation of hsp72 was induced by PKC and PKA activators [10]. 

            The existence of stress proteins in many species certainly argues for a central role for these proteins in fundamental cell processes, and heat shock protein induction has, in fact, been explored in relationship to a number of basic cellular phenomena.  Many stress proteins seem to function as molecular chaperones by regulating protein folding (for a review, see [11]), while others play a role in regulating the function of receptors such as the glucocorticoid receptor [12].

            Stress proteins may also play a role in cell death, and possibly in oncogenic transformation.  For example, hsp70 has been reported to confer some degree of resistance to apoptosis in lymphoid and myeloid cell lines [13].  Fragments of hsp70 can reduce cytochrome C [14].  Hsp70 may also prevent quercetin-induced apoptosis [15], and expression of hsp27 in tumorigenic mouse fibroblasts reduced the cytotoxicity of TNF-a to these cells [16]; [17]. 

            Hsp90 forms complexes with members of the cellular src family of tyrosine kinases, binding and altering kinase structure [18] and may be a participant in src-mediated oncogenic transformation [19].  A member of the hsp90 family has also been shown to be constitutively expressed in drug-resistant cancer cells, and may be involved in stabilization of the function of the P-glycoprotein molecule involved in multidrug resistance [20].

References:

1.   Moseley, P.L., Heat shock proteins and heat adaptation of the whole organism. J. Appl. Physiology, 1997. 83(5): p. 1413-1417.

2.   Tissieres, A., H.K. Mitchell, and U.M. Tracy, Protein synthesis in salivary glands of Drosophila melanogaster:  relation to chromosome puffs. J. of Molecular Biology, 1974. 84(3): p. 389-98.

3.   Morimoto, R.I., et al., The heat shock response:  regulation and function of heat-shock proteins and molecular chaperones. Essays in Biochemistry, 1997. 32: p. 17-29.

4.   Bauman, J.W., J. Liu, and C.D. Klaassen, Production of metallothionein and heat-shock proteins in response to metals. Fundamental and Applied Toxicology, 1993. 21: p. 15-22.

5.   Drummond, I.A. and R.A. Steinhardt, The role of oxidative stress in the induction of Drosophila heat-shock proteins. Experimental Cell Research, 1987. 173(2): p. 439-449.

6.   Myrmel, T., et al., Heat-shock protein 70 mRNA is induced by anaerobic metabolism in rat hearts. Circulation, 1994. 90: p. 299-305.

7.   Lindquist, S. and E.A. Craig, The Heat Shock Proteins. Annual Reviews of Genetics, 1988. 22: p. 631-677.

8.   Welch, W.J., Mammalian Stress Response:  Cell Physiology, Structure/ Function of Stress Proteins, and Implications of Medicine and Disease. Physiological Reviews, 1992. 72(4): p. 1063-1081.

9.   Li, G.C. and Z. Werb, Correlation between synthesis of heat shock proteins and development of thermotolerance in chinese hamster fibroblasts. PNAS, 1982. 79(3218-3222).

10. Ohnishi, K., et al., Contribution of protein kinase C to p53-dependent WAF1 induction pathway after heat treatment in human glioblastoma cell lines. Experimental Cell Research, 1998. 238(2): p. 399-406.

11. Hendrick, J.P. and F.-U. Hartl, Molecular chaperone functions of heat-shock proteins. Annu. Rev. Biochem., 1993. 62: p. 349-384.

12. Pratt, W.B., K.A. Hutchison, and L.C. Scherrer, Steroid Receptor Folding by Heat-Shock Proteins and Composition of the Receptor Heterocomplex. TEM, 1992. 3(9): p. 326-333.

13. Lasunskaia, E.B., et al., Accumulation of major stress protein 70kDa protects myeloid and lymphoid cells from death by apoptosis. Apoptosis, 1997. 2: p. 156-163.

14. Simpkins, C.O., K.W.I. Fogarty, and P. Nhamburo, Reduction of Cytochrome C by Fragments of Heat Shock Protein 70. Life Sciences, 1993. 52: p. 1487-1492.

15. Wei, Y.-q., et al., Induction of apoptosis by quercetin:  involvement of heat shock protein. Cancer Research, 1994. 54: p. 4952-4957.

16. Mehlen, P., et al., Constitutive expression of human hsp27, Drosophila hsp27, or human alphaB-crystallin confers resistance to TNF- and oxidative stress-induced cytotoxicity in stably transfected murine L929 fibroblasts. Immunology, 1995. 154: p. 363-374.

17. Jaattela, M., Over-expression of hsp70 confers tumorigenicity to mouse fibrosarcoma cells. Int. J. Cancer, 1995. 60: p. 689-693.

18. Hartson, S.D. and R.L. Matts, Association of hsp90 with cellular src-family kinases in a cell-free system correlates with altered kinase structure and function. Biochemistry, 1994. 33: p. 8912.

19. Whitesell, L., et al., Inhibition of heat shock protein HSP90-pp60^v-src heteroprotein complex formation by benzoquinone ansamycins:  essential role for stress proteins in oncogenic transformation. Proc. Natl. Acad. Sci., 1994. 91: p. 8324-8328.

20. Bertram, J., et al., Increase of P-glycoprotein-mediated drug resistance by hsp 90 beta. Anti-Cancer Drugs, 1996. 7: p. 838-845.