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| The EMBO Journal
(1999) 18, 5943–5952, doi:10.1093/emboj/18.21.5943 |
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| HSF1 is required for extra-embryonic development, postnatal growth and protection during inflammatory responses in mice |
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| XianZhong Xiao1, XiaoXia Zuo1, Alberta A. Davis1, D.Randy McMillan1, Bishop B. Curry2, James A. Richardson3 and Ivor J. Benjamin1, 4 |
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1 Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75235-8573, USA 2 Department of Comparative Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75235-8573, USA 3 Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX 75235-8573, USA 4 Division of Cell and Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75235-8573, USA To whom correspondence should be addressed Ivor J. Benjamin, ivor.benjamin@email.swmed.edu Received 4 August 1999; Revised 17 September 1999; Accepted 17 September 1999. |
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| Abstract |
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| HSF1 is the major heat shock transcriptional factor that binds heat shock element (HSE) in the promoter of heat shock proteins (Hsps) and controls rapid Hsp induction in cells subjected to various environmental stresses. Although at least four members of the vertebrate HSF family have been described, details of their individual physiological roles remain relatively obscure. To assess whether HSF1 exhibited redundant or unique in vivo functions, we created Hsf1-/- deficient mice. We demonstrate that homozygous Hsf1-/- mice can survive to adulthood but exhibit multiple phenotypes including: defects of the chorioallantoic placenta and prenatal lethality; growth retardation; female infertility; elimination of the 'classical' heat shock response; and exaggerated tumor necrosis factor alpha production resulting in increased mortality after endotoxin challenge. Because basal Hsp expression is not altered appreciably by the HSF1 null mutation, our findings suggest that this factor, like Drosophila Hsf protein, might be involved in regulating other important genes or signaling pathways. Our results establish direct causal effects for the HSF1 transactivator in regulating critical physiological events during extra-embryonic development and under pathological conditions such as sepsis to modulate pro-inflammatory responses, indicating that these pathways have clinical importance as therapeutic targets in humans. |
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| Keywords: development, heat shock, HSF, inflammation, stress response |
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