Zebrafish And Hsps

A variety of heat shock proteins and the heat shock transcription factor Hsf1 have been identified and cloned from zebrafish (Krone et al., 1994; Graser et al., 1996; Lele et al., 1997b; Santacruz et al., 1997; Rabergh et al., 2000). Many of these heat shock genes exhibit complex patterns of constitutive and inducible expression during embryonic development (Krone et al., 1997). For example, the Hsp90alpha gene is expressed at low levels constitutively but is strongly upregulated during heat shock, whereas Hsp90beta is expressed at much higher levels constitutively but is only weakly induced following heat shock in all stages of development examined in zebrafish embryos (Krone et al., 1994). Hsp70 and Hsp47 mRNA levels have also been shown to increase dramatically in response to heat stress, whereas the constitu-tively expressed heat shock cognate hsc70 exhibits only a slight increase. In contrast, exposure of zebrafish embryos to ethanol strongly induced Hsp47 but not Hsp70, demonstrating a differential response of the Hsps in zebrafish embryos (Lele et al., 1997a). Two isoforms of Hsf1, termed zHsf1a and zHsf1b, have been identified and cloned in zebrafish and are expressed in a tissue-specific fashion upon exposure to heat stress. Specifically, both forms are expressed in the gonads under all conditions, but in the liver zHsf1a is increased with heat shock whereas zHsf1b is decreased, indicating a unique, tissue-specific regulation of Hsf1 upon exposure to increased temperatures (Rabergh et al., 2000).

We have shown that mature zebrafish respond to heat shock with both nuclear translocation of Hsf1 and production of several Hsps in a variety of tissues (Murtha et al., 2003a), similar to what has been reported in other species. More specifically, we found that Hsp70 and Hsp47 were induced in response to heat stress in a tissue-specific manner, while Hsp90a, Hsp90ß, and Hsf1 were expressed constitutively and not induced by heat stress. Though Hsf1 RNA levels did not change with heat stress, Hsf1 protein translocated to the nucleus following heat stress, indicating activation of this transcription factor. Mammalian species show a similar pattern of Hsp and Hsf expression and Hsf activation in response to heat stress (Santoro, 2000). Furthermore, we found that aging modulates heat shock responsiveness and Hsp70 expression in zebrafish. Specifically, both basal and induced levels of Hsp70 were less in mature versus young zebrafish, which is consistent with previous reports in a variety of other species (Heydari et al., 1994; Kregel et al., 1995; Lee et al., 1996; Liu et al., 1996; Pahlavani et al., 1996). We also observed that Hsf1 mRNA levels were elevated in mature compared to young zebrafish and that heat shock did not induce Hsf1 mRNA expression in either age group but did induce nuclear translocation. This is also consistent with previous reports on Hsf1 expression and induction in other species (Locke et al., 1996; Heydari et al., 2000; Locke, 2000), in which Hsp70 levels are diminished with age in the face of increased Hsf1 levels, which is thought to be due to a decreased ability of Hsf1 to bind DNA in aged animals. This provides evidence that zebrafish can serve as a novel vertebrate model to study the mechanisms of aging and response to environmental stress. In addition, these results also have the potential to elucidate the mechanisms underlying many disease processes which show abnormal Hsp expression, including atherosclerosis, congestive heart failure, fever, infection, Alzheimer's disease, cancer, and autoimmune disease (Whitley et al., 1999).

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