Mouse heat-shock factor 1 (HSF1) is involved in testicular response to genotoxic stress induced by doxorubicin

Heat-shock factor 1 (HSF1) protects cells and organisms against various types of stress, either by triggering a complex response that promotes cell survival or by triggering cell death when stress-induced alterations cannot be rescued. Although this dual role of HSF1 was observed in spermatogenesis exposed to heat shock or proteotoxic stress, HSF1 was also reported to contribute to cell resistance against genotoxic stress, such as that caused by doxorubicin, an anticancer drug in common clinical use. To better understand the stress/cell-dependent functions of HSF1, we used wild-type and Hsf1(tm1Ijb)/Hsf1(tm1Ijb) males to determine the role of HSF1 in the genotoxic stress response elicited in spermatogenic cells. Within 2 days after a single intraperitoneal injection of doxorubicin (DOXO; 5 mg/kg), proliferation of Hsf1+/+ but not Hsf1-/- spermatogenic cells was significantly reduced, whereas cell death was increased in mitotic germ cells and metaphase I spermatocytes. By 21 days, meiotic cells were depleted in all treated Hsf1+/+ testes but not in Hsf1-/- ones. Nevertheless, after 3 mo, spermatogenesis showed better signs of recovery in Hsf1+/+ than in Hsf1-/- males. Taken together, these data indicate that acute response to genotoxic stress in the testis involves HSF1-dependent mechanisms that induce apoptotic cell death in a TRP53-independent manner, but also intervene on a longer term to restore seminiferous tubules.     

HSF1 activation occurs at different temperatures in somatic and male germ cells in the poikilotherm rainbow trout.

The heat shock factor 1 (HSF1) is the central actor of the response to hyperthermia in eukaryotic cells. In mammals, male germ cells are an exception among all cellular populations for their HSF1 activation occurs at low temperature. This feature was believed to be specific of homeotherms whose testicular compartment is located outside the main body cavity, where temperature is lower. In the present study, we show that in the poikilotherm rainbow trout, the maximal heat shock response of male germ cells, that are located in the same body compartment than the other organs, occurs also at a significantly lower temperature (22 degrees C) than for somatic cells (28 degrees C), regardless of culture conditions before heat shock. In addition, the acquisition of the HSE-binding activity of HSF1 upon heat shock is not associated with the classical hsp70 mRNA accumulation. Taken together, these results strongly suggest the existence of a particular mode of heat shock response that could be specific of male germ cells but not restricted to homeotherms.     

CHIP interacts with heat shock factor 1 during heat stress

Heat shock factor 1 (HSF1) is a major transactivator of heat shock genes in response to stress and mediates cell protection against various harmful conditions. In this study, we identified the interaction of CHIP (carboxyl terminus of the heat shock cognate protein 70-interacting protein) with the N-terminus of HSF1. Using GST full-down assay, we found that CHIP directly interacts with C-terminal deleted HSF1 (a.a. 1-290) but not with full-length HSF1 under non-stressed conditions. Interestingly, interaction of CHIP with full-length HSF1 was induced by heat shock treatment. The structural change of HSF1 was observed under heat stressed conditions by CD spectra. These observations demonstrate the direct interaction between HSF1 and CHIP and this interaction requires conformational change of HSF1 by heat stress.     

Heat shock proteins in mammalian development

Mammalian development follows a defined but adjustable program, depending on the plasticity of embryonic cells 'response to environmental changes. Heat shock proteins (Hsp) are integral part of this developmental program and gene targeting experiments have started to unravel developmental processes, which exhibit specific requirements for Hsps (e.g. Hsp70.2 for spermatogenesis). In the present paper, we will review available data on Hsp function and discuss the roles of heat shock factors (HSF), their major regulators, in mammalian development.