Impaired camp-mediated gene expression and decreased camp response
element binding protein in senescent cells.
Chin, Jane H., Masahiro Okazaki, James S. Frazier, Zhuo-Wei Hu, and
Brian B. Hoffman.
Departments of Medicine and Psychiatry, Stanford University School
of Medicine, and Geriatric Research, Educational, and Clinical
Center, and Psychiatry Service, VA Medical Center, Palo Alto,
California 94304
APStracts 3:0077C, 1996.
The capacity of various growth factors to induce c-fos expression is
diminished with senescence. Since 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.
Received 22 September 1995; accepted in final form 17 January
1996.
APS Manuscript Number C574-5.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 20 March 96