The stress response is an evolutionarily conserved cellular response mechanism characterized by the enhanced synthesis and accumulation of heat shock proteins (Hsps). These proteins act as molecular chaperones and prevent aggregation of misfolded proteins;they also assist in the refolding, transport, and assembly of proteins in the cytoplasm, mitochondria and endoplasmic reticulum. There is widespread clinical interest in Hsp chaperone function in a number of human pathologies including cancer, neurodegenerative conditions, aging, and cardiovascular diseases. Our understanding of Hsp function in pathological situations has been greatly advanced by the development of mutant mouse models. In this grant the major goal is to define a framework of interactions between three major heat shock proteins, constitutive HscVO, its inducible counterpart HspVOi and the small molecular weight Hsp27 (mouse Hsp25), which play intimate roles in tumor development by modulating endothelial cell differentiation and thus neoangiogenesis, and by affecting molecular pathways for cell survival/death. Mutant mice deficient in these heat shock proteins generated by conventional or conditional gene targeting strategies offer unique opportunities to address these important issues in the cancer biology at the whole organism level. During the next project period we plan to follow two aims: (1) To define the functional contribution of HspVOi, HscVO or Hsp25 in tumor vasculogenesis and/angiogenesis. (2) To characterize the physiological roles of Hsp70i, Hsc70, and Hsp25 in regulating the stress response and define their contribution to tumor development in vivo. The proposed studies will help to achieve a better understanding of the fundamental cellular processes in which these molecular chaperones engage to promote tumor growth, and may help to develop strategies to modulate specific chaperone-dependent host pathways as a therapeutic approach to combat human cancers and other relevant diseases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZRG1-ONC-N (02))
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Ault, Grace S
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Georgia Regents University
Internal Medicine/Medicine
Schools of Medicine
United States
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Jin, Xiongjie; Eroglu, Binnur; Moskophidis, Demetrius et al. (2018) Targeted Deletion of Hsf1, 2, and 4 Genes in Mice. Methods Mol Biol 1709:1-22
Eroglu, Binnur; Min, Jin-Na; Zhang, Yan et al. (2014) An essential role for heat shock transcription factor binding protein 1 (HSBP1) during early embryonic development. Dev Biol 386:448-60
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Jin, Xiongjie; Eroglu, Binnur; Moskophidis, Demetrius et al. (2011) Targeted deletion of Hsf1, 2, and 4 genes in mice. Methods Mol Biol 787:1-20
Jin, Xiongjie; Moskophidis, Demetrius; Mivechi, Nahid F (2011) Heat shock transcription factor 1 is a key determinant of HCC development by regulating hepatic steatosis and metabolic syndrome. Cell Metab 14:91-103
Eroglu, Binnur; Moskophidis, Demetrius; Mivechi, Nahid F (2010) Loss of Hsp110 leads to age-dependent tau hyperphosphorylation and early accumulation of insoluble amyloid beta. Mol Cell Biol 30:4626-43
Jin, Xiongjie; Moskophidis, Demetrius; Hu, Yanzhong et al. (2009) Heat shock factor 1 deficiency via its downstream target gene alphaB-crystallin (Hspb5) impairs p53 degradation. J Cell Biochem 107:504-15
Huang, Lei; Min, Jin-Na; Masters, Shane et al. (2007) Insights into function and regulation of small heat shock protein 25 (HSPB1) in a mouse model with targeted gene disruption. Genesis 45:487-501

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