Immortalization of Human Mammary Epithelial Cells Is Associated with Inactivation of the p14ARF-p53 Pathway

Vladimir A. Shamanin, Elliot J. Androphy

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Inactivation of the ARF-p53 tumor suppressor pathway leads to immortalization of murine fibroblasts. The role of this pathway in immortalization of human epithelial cells is not clear. We analyzed the functionality of the p14ARF-p53 pathway in human mammary epithelial cells (MEC) immortalized by human papillomavirus 16 (HPV16) E6, the p53 degradation-defective E6 mutant Y54D, or hTERT. E6-MEC or E6Y54D-MEC maintains high-level expression of p14ARF. Late-passage hTERT-immortalized MEC express p53 but down-regulate p14ARF. Enforced expression of p14 ARF induces p53-dependent senescence in hTERT-MEC, while both E6-MEC and E6Y54D-MEC are resistant. We show that E6Y54D inhibits p14 ARF-induced activation of p53 without inactivation of the p53-dependent DNA damage response. Hence, p53 degradation and inhibition of p14ARF signaling to p53 are independent functions of HPV16 E6. Our observations imply that long-term proliferation of MEC requires inactivation of the p14ARF-p53 pathway.

Original languageEnglish (US)
Pages (from-to)2144-2152
Number of pages9
JournalMolecular and cellular biology
Volume24
Issue number5
DOIs
StatePublished - Mar 1 2004

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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