HSP70-2 HEAT-SHOCK-PROTEIN OF MOUSE SPERMATOGENIC CELLS

The HSP70 heat-shock proteins are molecular chaperones that assist oth er proteins in folding, transport, and assembly into complexes. The ge nes for these proteins are either constitutively expressed (Hsc70, Grp 78), or their expression is induced by heat shock and other stresses ( Hsp 70-1, Hsp 70-3). Two additional genes encode proteins that are dev elopmentally regulated and expressed specifically in spermatogenic cel ls (Hsp 70-2, Hsc70t). The HSP70-2 protein is synthesized during the m eiotic phase of spermatogenesis and is abundant in pachytene spermatoc ytes. Studies in transgenic mice indicated that the region between nuc leotides -640 and +1 contains promoter sequences necessary for express ion of Hsp70-2 in spermatocytes. Because of the pattern of gene expres sion, it was hypothesized that HSP70-2 is a chaperone necessary for co mpletion of meiosis in spermatogenic cells. The gene knockout approach was used to test this hypothesis, and it was found that male mice hom ozygous for the mutation were infertile, whereas homozygous females we re fertile. Spermatogenesis was disrupted, with the nuclei of late pac hytene spermatocytes often appearing fragmented and spermatids being a bsent. Disruption of spermatogenesis occurred at the G(2)-M phase tran sition in prophase of meiosis I, and all pachytene spermatocytes under went apoptosis. It was demonstrated that HSP70-2 is a chaperone for Cd c2, with their association allowing Cdc2 to acquire the necessary conf ormation to form a heterodimer with cyclin B-1, leading to changes in Cdc2 phosphorylation and the development of kinase activity necessary for the G2-M phase transition. This appears to be the first demonstrat ion that interaction between an HSP70 protein and a cyclin-dependent k inase is necessary for progression of the cell cycle. J. Exp. Zool. 28 2:261-271, 1998. (C) 1998 Wiley-Liss, Inc.dagger.