HSF4 is required for normal cell growth and differentiation during mouse lens development
HSF4 is required for normal cell growth and differentiation during mouse lens development
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DOI：
10.1038/sj.emboj.7600435
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发表时间：
2004-10-27
期刊：
影响因子：
11.4
通讯作者：
Nakai, A
中科院分区：
文献类型：
--
作者：
Fujimoto, M;Izu, H;Nakai, A
热休克转录因子（HSF）家族在哺乳动物中有三个成员，它们通过热休克元件调控热休克基因的表达。HSF1和HSF2参与某些发育过程，但它们如何调控这些过程尚不清楚。为了阐明HSF对发育调控的机制，我们培育出HSF4基因突变的小鼠。HSF4基因敲除小鼠患有白内障，其晶状体纤维细胞异常，含有包涵体样结构，这可能是由于维持蛋白质稳定性的γ - 晶状体蛋白表达降低所致。此外，我们发现突变的晶状体上皮细胞增殖增加且分化提前，这与生长因子FGF - 1、FGF - 4和FGF - 7的表达增加有关。出乎意料的是，HSF1不仅在晶状体中，而且在其他组织中与HSF4竞争FGFs的表达。这些研究结果揭示了HSF4激活γ - 晶状体蛋白基因这一晶状体特异性作用，同时也表明HSF1和HSF4参与调控对细胞生长和分化至关重要的生长因子基因的表达。
The heat shock transcription factor (HSF) family consists of three members in mammals and regulates expression of heat shock genes via a heat shock element. HSF1 and HSF2 are required for some developmental processes, but it is unclear how they regulate these processes. To elucidate the mechanisms of developmental regulation by HSFs, we generated mice in which the HSF4 gene is mutated. HSF4-null mice had cataract with abnormal lens fiber cells containing inclusion-like structures, probably due to decreased expression of gamma-crystallin, which maintains protein stability. Furthermore, we found increased proliferation and premature differentiation of the mutant lens epithelial cells, which is associated with increased expression of growth factors, FGF-1, FGF-4, and FGF-7. Unexpectedly, HSF1 competed with HSF4 for the expression of FGFs not only in the lens but also in other tissues. These findings reveal the lens-specific role of HSF4, which activates gamma-crystallin genes, and also indicate that HSF1 and HSF4 are involved in regulating expression of growth factor genes, which are essential for cell growth and differentiation.