Understanding the physiological function of heat shock transcription factors using animal models.

摘要

Heat shock factor family (Hsf1, Hsf2, and Hsf4 in mammals) is a transcriptional activator and all Hsfs bind to unique cis-acting promoter elements, called heat shock elements (HSEs) which are composed of an inverted repeat of nGAAn and activate downstream target genes [1] [2]. Among Hsfs, Hsf1 controls expression of heat shock protein (Hsp) genes by binding to HSEs located in promoter of such genes in response to various stresses such as heat shock [1]. Hsps, also known as molecular chaperones, function in protein folding, trafficking, maturation, degradation and signal transduction [3, 4]. In addition, several studies indicate that Hsps play a role as anti-apoptotic molecules. Overexpression of certain Hsps is correlated with resistance to cancer therapy including chemo- and radiotherapy in certain human cancers, which indicates there is a close relationship between altered expression of Hsps and cancer [5]. The cell protective function of Hsf1, by increase in the level of Hsps, is extensively studied in cell culture system as well as in mice deficient in Hsf1 gene under stress conditions, especially following exposure to elevated temperature [6-8]. Even though physiological function of Hsf1 has been studied using Hsf1 knockout mouse model, function of Hsf1 and its target genes, such as the Hsps, in tumor development remains elusive.; Other mammalian Hsfs, Hsf2 and Hsf4 are known to be activated during normal development and differentiation [9-12]. Moreover, the expression of Hsf2 or Hsf4 gene is restricted in certain tissues suggesting that Hsf2 and Hsf4 have distinct function in different tissues [12, 13]. However, compared to Hsf1, Hs12 and Hsf4 are not well investigated in terms of the mode of their activation and their downstream target genes. In addition, Hsf2 and Hsf4 physiological function in vivo are unknown. Recently, the genetic linkage study has shown that mutations in the Hsf4 gene are associated with inherited human cataract (lamellar and Marner cataract) [14]. The mutations on the Hsf4 gene are located in DNA binding domain of Hsf4, which indicates that transcriptional activity of Hsf4 is defective in patients with cataract [14]. These data suggest that Hsf4 and its target genes will have a critical function in eye development.; Based on recent studies, specific aims of my project are; Aim I. To understand the physiological function of Hsf1 and inducible Hsps during tumor development using Hsf1 and p53 knockout mouse models. Aim II. To characterize the physiological role and target genes of Hsf4 during eye development using Hsf4 knockout mouse model.