Expression of human papilloma virus E7 protein causes apoptosis and inhibits DNA synthesis in primary hepatocytes via increased expression of p21(Cip-1WAF1/MDA6)

Jong Sung Park, Sarah Boyer, Kyran Mitchell, Donna Gilfor, Michael Birrer, Gretchen Darlington, Wafik El Deiry, Gary L. Firestone, Karl Munger, Vimla Band, Paul B. Fisher, Paul Dent

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The impact of human papilloma virus (HPV16) E7 proteins and retinoblastoma (RB) antisense oligonucleotides upon mitogen-activated protein kinase (MAPK)-mediated inhibition of DNA synthesis via p21(Cip-1/WAF1/MDA6) (p21) was determined in primary hepatocytes. Prolonged activation of the MAPK pathway in p2(1+/+) or p21(-/-) hepatocytes caused a large decrease and increase, respectively, in DNA synthesis. Either transfection with RB antisense oligonucleotides, expression of wild type E7, or RB binding mutant E7 (C24S) proteins increased p21 levels and reduced DNA synthesis in p21(+/+) hepatocytes. RB antisense oligonucleotides and E7 proteins increased apoptosis in p21(+/+), but not p21(-/-), hepatocytes. Expression of wild type E7 increased DNA synthesis above control levels in p21(-/-) cells, which was additive with prolonged MAPK activation. In contrast, expression of mutant E7 did not alter DNA synthesis above control levels in p21(-/-) cells and was supra-additive with prolonged MAPK activation. Antisense ablation of RB in p21(-/-) hepatocytes had a weak stimulatory effect upon DNA synthesis itself but enhanced the capacity of mutant E7 protein to stimulate DNA synthesis to the same level observed using wild type E7. The ability of prolonged MAPK activation to stimulate DNA synthesis in the presence of mutant E7 and antisense RB was additive. Collectively, the present data demonstrate that loss of RB function together with loss of p21 function plays an important role in the E7-and MAPK-dependent modulation of apoptosis and DNA synthesis in primary hepatocytes.

Original languageEnglish (US)
Pages (from-to)18-28
Number of pages11
JournalJournal of Biological Chemistry
Volume275
Issue number1
DOIs
StatePublished - Jan 7 2000
Externally publishedYes

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Papillomaviridae
Viruses
Retinoblastoma
Hepatocytes
Apoptosis
Mitogen-Activated Protein Kinases
DNA
Proteins
Antisense Oligonucleotides
Chemical activation
Level control
Mutant Proteins
Ablation
Transfection

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Expression of human papilloma virus E7 protein causes apoptosis and inhibits DNA synthesis in primary hepatocytes via increased expression of p21(Cip-1WAF1/MDA6). / Park, Jong Sung; Boyer, Sarah; Mitchell, Kyran; Gilfor, Donna; Birrer, Michael; Darlington, Gretchen; El Deiry, Wafik; Firestone, Gary L.; Munger, Karl; Band, Vimla; Fisher, Paul B.; Dent, Paul.

In: Journal of Biological Chemistry, Vol. 275, No. 1, 07.01.2000, p. 18-28.

Research output: Contribution to journalArticle

Park, JS, Boyer, S, Mitchell, K, Gilfor, D, Birrer, M, Darlington, G, El Deiry, W, Firestone, GL, Munger, K, Band, V, Fisher, PB & Dent, P 2000, 'Expression of human papilloma virus E7 protein causes apoptosis and inhibits DNA synthesis in primary hepatocytes via increased expression of p21(Cip-1WAF1/MDA6)', Journal of Biological Chemistry, vol. 275, no. 1, pp. 18-28. https://doi.org/10.1074/jbc.275.1.18
Park, Jong Sung ; Boyer, Sarah ; Mitchell, Kyran ; Gilfor, Donna ; Birrer, Michael ; Darlington, Gretchen ; El Deiry, Wafik ; Firestone, Gary L. ; Munger, Karl ; Band, Vimla ; Fisher, Paul B. ; Dent, Paul. / Expression of human papilloma virus E7 protein causes apoptosis and inhibits DNA synthesis in primary hepatocytes via increased expression of p21(Cip-1WAF1/MDA6). In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 1. pp. 18-28.
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AU - El Deiry, Wafik

AU - Firestone, Gary L.

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