Differential regulation of hepatocyte dna synthesis by camp in
vitro and in vivo .
Westwick, Jk, J Fleckenstein, M Yin, Sq Yang, Ca Bradham, Da Brenner,
Am Diehl.
Department of Pharmacology and Lineberger Comprehensive Cancer
Center, University of North Carolina, Chapel Hill, NC 27599-7365,
Department of Medicine, Johns Hopkins University, Baltimore, MD and
Departments of Medicine and Biochemistry and Biophysics, University
of North Carolina, Chapel Hill, NC 27599-7080
APStracts 3:0099G, 1996.
Cyclic AMP prevents epidermal growth factor (EGF)-induced DNA
synthesis in many types of cultured cells including hepatocytes, but
its effects on cellular proliferation in vivo are unknown. This
study: 1) compares the effects of supplemental cAMP on hepatocyte
proliferation induced in vivo by 70% partial hepatectomy (PH) and in
vitro by epidermal growth factor (EGF), and 2) determines the effects
of cAMP on AP-1, a family of growth-regulatory transcription factors,
and the kinase cascades which normally activate AP-1. Although
injection of dibutyryl cAMP (30 mg/kg i.p.) at the time of PH
increased liver cAMP concentrations at least 100 fold for several
hours, it did not inhibit hepatic incorporation of [3H] thymidine or
PCNA expression 24 h after PH. cAMP treatment led to a complete
inhibition of ERK activity and transiently reduced Jun N-terminal
Kinase (JNK) activity after PH but did not decrease the expression of
c-jun mRNA or protein. Consistent with the known cAMP stimulation of
junB in cultured cells, cAMP treatment increased junB mRNA, protein
and DNA binding activity post-PH. Surprisingly, cAMP treatment
enhanced Raf kinase activity after PH in rats. In primary hepatocyte
cultures, supplemental cAMP inhibited JNK and ERK activity, total AP
-1 and c-Jun transcriptional activities, and DNA synthesis. Thus,
elevated cAMP inhibited ERK and JNK activity in culture and in vivo,
and inhibited hepatocyte proliferation in culture but not in vivo.
This suggests that in vivo mechanisms compensate for cAMP inhibition
of certain growth-related signaling cascades and emphasizes potential
risks of extrapolating from simple cell culture systems to explain
physiology in intact animals.
Received 3 January 1996; accepted in final form 19 April 1996.
APS Manuscript Number G7-6.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 8 May 96