AJP - Cell Physiology, Vol 271, Issue 1 C362-C371, Copyright © 1996 by American Physiological Society
Impaired cAMP-mediated gene expression and decreased cAMP response element binding protein in senescent cells
J. H. Chin, M. Okazaki, J. S. Frazier, Z. W. Hu and B. B. Hoffman
Department of Medicine, Stanford University School of Medicine, California, USA.
The capacity of various growth factors to induce c-fos expression is
diminished with senescence. Because adenosine 3',5'-cyclic monophosphate
(cAMP)-mediated responses are also blunted with aging, we wondered whether
cAMP-induced c-fos gene expression might be impaired with senescence. Using
IMR fibroblasts, we found that prostaglandin E1 (PGE1) and forskolin,
stimulators of cAMP accumulation in young and senescent cells, increased
abundance of c-fos and junB mRNA more in young than senescent cells. The
abundance of the cAMP response element binding protein (CREB), a
transcription factor which enhances gene expression when phosphorylated by
protein kinase A, was markedly decreased in both whole cell and nuclear
extracts of senescent cells, in both Western blotting and in gel
retardation assays. Also, PGE1-induced phosphorylation of CREB by protein
kinase A was markedly attenuated in senescent cells. There is a marked
decrement in expression of CREB with senescence, and the results suggest
the possibility that the diminished expression of CREB may contribute to
altered cAMP-mediated regulation of gene expression with senescence.
