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- Welsh Lab: 734 763 9511 3818 BSRB
- UMICH Directory (MCommunity)
EducationPH.D. University of Western Ontario M.S. Texas A & M University, College Station, Texas
Cell biology of small heat shock proteins
My laboratory is interested in the role of the low molecular weight heat-shock proteins family, particularly hsp27, in mechanisms of toxicity in the testis and in differentiation and development of muscle tissues.
We have shown in the testis that in vivo cadmium treatment results in failure of spermiation as well as changes in Sertoli cell microfilaments at stages VII-XI of the cycle of the seminiferous epithelium, the period of time during which expression of hsp27 is lowest. Because hsp27 has been shown to protect cells from the effects of many toxicants including cadmium, we hypothesize that the particular sensitivity of the seminiferous epithelium during stages VII-XI of the cycle is a result of low hsp27 expression. We have observed that hsp27 co-localizes with microfilaments of differentiated Sertoli cells. Overall, these results suggest that the effect of cadmium on spermatogenesis may involve Sertoli cell hsp27 and microfilament structure/function. Because only differentiated Sertoli cells exhibit colocalization of hsp27 with microfilaments we hypothesize that hsp27 binding to microfilaments is mediated by another protein. Using the yeast two-hybrid system, we have discovered several new hsp27-binding proteins that may mediate hsp27-microfilament interaction. These new proteins are being characterized.
Expression of hsp27 has been observed to increase significantly in many cells types and tissues as they differentiate. Hsp27 is expressed at the highest levels of any tissues in muscle. The presence of muscle-specific transcriptional regulatory sequences in the hsp27 gene imply that hsp27 expression in muscle is controlled in a tissue-specific manner, and studies of a cell line that differentiates into striated muscle in culture as well as examination of hsp27 expression in rat embryos show that hsp27 is one of the earliest proteins expressed in differentiating muscle. Further, phosphorylation of hsp27 has been shown to correlate with smooth muscle contraction, while phosphorylation of hsp20 (another member of the small heat-shock protein family) correlates with smooth muscle relaxation. We hypothesize that hsp27 is necessary for all types of muscle differentiation and function. To further study the potential role of hsp27 in muscle differentiation and function, we are developing transgenic mice that express human hsp27 and mutant hsp27 proteins that have their phosphorylation sites changed from serines to either aspartates, glycines or alanines. These transgenic animals will also be used to study the role of hsp27 in Sertoli cell function and spermatogenesis and mechanisms of toxicant action in the testis.
We have recently discovered a new member of the small heat-shock protein family. It is a phosphoprotein and is expressed most highly, and possibly exclusively, in muscle. Studies are underway to define the protein kinase(s) responsible for phosphorylation of this new protein and to learn the function of the protein. In collaboration with Dr. William Smoyer (U of M, Department of Pediatrics), we are studying a rat animal model for nephrotic syndrome, a common kidney disease of children. We have discovered that hsp27 is highly expressed in glomerular epithelial cells of the rat kidney and that increased expression and phosphorylation of hsp27 correlates with the development of nephrotic syndrome in the rat. We are also collaborating with Dr. John Williams (U of M Department of Physiology) in studies of the role of hsp27 in pancreatic acinar cell function. In this collaboration, we have made transgenic animals that express human hsp27 only in pancreatic acinar cells. These animals as well as cells derived from these animals are being studied.
- Liu C, Gilmont RR, Benndorf R, Welsh MJ: Identification and characterization of a novel protein from Sertoli cells, PASS1, that associates with mammalian small stress protein hsp27. J Biol Chem 2000 Jun 23;275(25):18724-31.
- Smoyer WE, Ransom R, Harris RC, Welsh MJ, Lutsch G, Benndorf R: Differential accumulation and phosphorylation of hsp27 and aB-crystallin following acute renal ischemia. J Am Soc Nephrol 2000 Feb;11(2):211-21
- Schafer C, Clapp P, Welsh MJ, Benndorf R, Williams JA: Hsp27 expression and phosphorylation regulates cholecystokinin-induced changes in the actin cytoskeleton in CHO-CCK-A cells. Am J Physiol 1999 Dec;277(6 Pt 1):C1032-43
- Ibitayo AI, Sladick J, Tuteja S, Louis-Jacques O, Yamada H, Groblewski G, Welsh M, Bitar KN: HSP27 in signal transduction and association with contractile proteins in smooth muscle cells. Am J Physiol 1999 Aug;277(2 Pt 1):G445-54.
- Liu C, Welsh MJ: Identification of a site of Hsp27 binding with Hsp27 and alpha B-crystallin as indicated by the yeast two-hybrid system. Biochem Biophys Res Commun. 1999 Feb 16;255(2):256-61.
- Welsh MJ, Gaestel M: Small heat shock protein family: function in health and disease. Ann N Y Acad Sci. 1998 Jun 30;851:28-35.
- Smoyer WE, Mundel P, Gupta A, Welsh MJ: Podocyte a-actinin induction precedes foot process effacement in experimental nephrotic syndrome. Am J Physiol. 1997 Jul;273(1 Pt 2):F150-7.
- Methods in Gene Biotechnology, by W Wu, MJ Welsh, PB Kaufman and HH Zhang. CRC Press, Boca Raton, FL. pp 406. 1997.
- Wu W, Welsh MJ: Expression of the 25-kDa heat-shock protein (HSP27) correlates with resistance to the toxicity of cadmium chloride, mercuric chloride, cis-platinum(II)-diammine dichloride, or sodium arsenite in mouse embryonic stem cells transfected with sense or antisense HSP27 cDNA. Toxicol Appl Pharmacol. 1996 Nov;141(1):330-9.
- Mirkes PE, Little SA, Cornel L, Welsh MJ, Laney TN, Wright FH: Induction of heat shock protein 27 in rat embryos exposed to hyperthermia. Mol Reprod Dev. 1996 Nov;45(3):276-84.
- Smoyer WE, Gupta A, Mundel P, Ballew JD, Welsh MJ: Altered expression of glomerular heat shock protein 27 in experimental nephrotic syndrome. J Clin Invest. 1996 Jun 15;97(12):2697-704.
- Welsh MJ, Wu W, Parvinen M, Gilmont RR: Variation in expression of hsp27 messenger ribonucleic acid during the cycle of the seminiferous epithelium and co-localization of hsp27 and microfilaments in Sertoli cells of the rat. Biol Reprod. 1996 Jul;55(1):141-51.