衰老
生物
下调和上调
基因表达
基因
细胞生物学
分子生物学
基因表达调控
DNA损伤
人口
细胞生长
细胞周期
基因产物
血清反应因子
遗传学
DNA
人口学
社会学
作者
Muthupalaniappan Meyyappan,Keith Wheaton,Karl Riabowol
标识
DOI:10.1002/(sici)1097-4652(199904)179:1<29::aid-jcp4>3.0.co;2-d
摘要
Human diploid fibroblasts (HDFs) undergo a limited number of population doublings in culture before reaching the end of their proliferative life span, an event termed in vitro cellular senescence. Considerable evidence suggests that altered expression of key genes involved in the mitogenic response may be responsible for the inability of senescent cells to proliferate. Here we examined the expression and activity of the early growth response-1 (egr-1) gene, an “immediate-early” gene that is believed to link extracellular mitogenic signals to cell-cycle progression. We found that egr-1 was strongly downregulated in senescent HDFs at the level of mRNA, protein, and DNA binding activity. Decreased DNA binding activity of Egr-1 in vitro corresponded to decreased transcriptional activation in vivo. To further understand the mechanism of egr-1 downregulation, we examined the potential role of the serum response elements (SREs) present in the egr-1 promoter. Electrophoretic mobility shift studies using young and old cell nuclear extracts showed a marked decrease in serum response factor (SRF) binding activity to the SRE in old compared to young cells. Loss of SRF binding activity has been correlated with the loss of expression of another growth-related immediate-early gene (c-fos). These results suggest a common mechanism for the downregulation of c-fos, egr-1, and other SRE-dependent, mitogen-responsive genes during cellular senescence. J. Cell. Physiol. 179:29–39, 1999. © 1999 Wiley-Liss, Inc.
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