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Differential regulation of hepatocyte DNA synthesis by cAMP in vitro in vivo.

Publication ,  Journal Article
Westwick, JK; Fleckenstein, J; Yin, M; Yang, SQ; Bradham, CA; Brenner, DA; Diehl, AM
Published in: Am J Physiol
November 1996

Adenosine 3',5'-cyclic monophosphate (cAMP) 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 compares the effects of supplemental cAMP on hepatocyte proliferation induced in vivo by 70% partial hepatectomy (PH) and in vitro by EGF and determines the effects of cAMP on AP-1, a family of growth-regulatory transcription factors, and the kinase cascades that normally activate AP-1. Although injection of dibutyryladenosine 3',5'-cyclic monophosphate (30 mg/kgip) 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 proliferating cell nuclear antigen expression 24 h after PH. cAMP treatment led to a complete inhibition of extracellular signal-related kinase (ERK) activity and transiently reduced NH2-terminal Jun nuclear kinase (JNK) activity after PH but did not decrease the expression of c-jun mRNA or protein. Consistent with the known cAMP stimulation of jun-B in cultured cells, cAMP treatment increased jun-B 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.

Duke Scholars

Published In

Am J Physiol

DOI

ISSN

0002-9513

Publication Date

November 1996

Volume

271

Issue

5 Pt 1

Start / End Page

G780 / G790

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Transcription Factor AP-1
  • Time Factors
  • Rats
  • RNA, Messenger
  • Proto-Oncogene Proteins c-raf
  • Proto-Oncogene Proteins c-jun
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Protein Kinases
 

Citation

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Westwick, J. K., Fleckenstein, J., Yin, M., Yang, S. Q., Bradham, C. A., Brenner, D. A., & Diehl, A. M. (1996). Differential regulation of hepatocyte DNA synthesis by cAMP in vitro in vivo. Am J Physiol, 271(5 Pt 1), G780–G790. https://doi.org/10.1152/ajpgi.1996.271.5.G780
Westwick, J. K., J. Fleckenstein, M. Yin, S. Q. Yang, C. A. Bradham, D. A. Brenner, and A. M. Diehl. “Differential regulation of hepatocyte DNA synthesis by cAMP in vitro in vivo.Am J Physiol 271, no. 5 Pt 1 (November 1996): G780–90. https://doi.org/10.1152/ajpgi.1996.271.5.G780.
Westwick JK, Fleckenstein J, Yin M, Yang SQ, Bradham CA, Brenner DA, et al. Differential regulation of hepatocyte DNA synthesis by cAMP in vitro in vivo. Am J Physiol. 1996 Nov;271(5 Pt 1):G780–90.
Westwick, J. K., et al. “Differential regulation of hepatocyte DNA synthesis by cAMP in vitro in vivo.Am J Physiol, vol. 271, no. 5 Pt 1, Nov. 1996, pp. G780–90. Pubmed, doi:10.1152/ajpgi.1996.271.5.G780.
Westwick JK, Fleckenstein J, Yin M, Yang SQ, Bradham CA, Brenner DA, Diehl AM. Differential regulation of hepatocyte DNA synthesis by cAMP in vitro in vivo. Am J Physiol. 1996 Nov;271(5 Pt 1):G780–G790.

Published In

Am J Physiol

DOI

ISSN

0002-9513

Publication Date

November 1996

Volume

271

Issue

5 Pt 1

Start / End Page

G780 / G790

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Transcription Factor AP-1
  • Time Factors
  • Rats
  • RNA, Messenger
  • Proto-Oncogene Proteins c-raf
  • Proto-Oncogene Proteins c-jun
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Protein Kinases