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Vol. 9, Issue 1, 15-28, January 1998
-Monophosphate Dehydrogenase Is a Rate-determining
Factor for p53-dependent Growth Regulation
The Molecular Oncology Group, Division of Medical Science, Fox
Chase Cancer Center, Philadelphia, Pennsylvania 19111
We have proposed that reduced activity of inosine-5
-monophosphate
dehydrogenase (IMPD; IMP:NAD oxidoreductase, EC 1.2.1.14), the
rate-limiting enzyme for guanine nucleotide biosynthesis, in response
to wild-type p53 expression, is essential for p53-dependent growth
suppression. A gene transfer strategy was used to demonstrate that
under physiological conditions constitutive IMPD expression prevents
p53-dependent growth suppression. In these studies, expression of
bax and waf1, genes implicated in
p53-dependent growth suppression in response to DNA damage, remains
elevated in response to p53. These findings indicate that under
physiological conditions IMPD is a rate-determining factor for
p53-dependent growth regulation. In addition, they suggest that the
impd gene may be epistatic to bax and
waf1 in growth suppression. Because of the role of IMPD
in the production and balance of GTP and ATP, essential nucleotides for
signal transduction, these results suggest that p53 controls cell
division signals by regulating purine ribonucleotide metabolism.
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