ΔNp73 facilitates cell immortalization and cooperates with oncogenic Ras in cellular transformation in vivo

Oleksi Petrenko, Alexander Zaika, Ute M. Moll

Research output: Contribution to journalArticle

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Abstract

TP73, despite significant homology to TP53, is not a classic tumor suppressor gene, since it exhibits upregulation of nonmutated products in human tumors and lacks a tumor phenotype in p73-deficient mice. We recently reported that an N-terminally truncated isoform, ΔNp73, is upregulated in breast and gynecological cancers. We further showed that ΔNp73 is a potent transdominant inhibitor of wild-type p53 and TAp73 in cultured human tumor cells by efficiently counteracting their target gene transactivations, apoptosis, and growth suppression functions (A. I. Zaika et al., J. Exp. Med. 6:765-780, 2002). Although these data strongly suggest oncogenic properties of ΔNp73, this can only be directly shown in primary cells. We report here that ΔNp73 confers resistance to spontaneous replicative senescence of primary mouse embryo fibroblasts (MEFs) and immortalizes MEFs at a 1,000-fold-higher frequency than occurs spontaneously. ΔNp73 cooperates with cMyc and E1A in promoting primary cell proliferation and colony formation and compromises p53-dependent MEF apoptosis. Importantly, ΔNp73 rescues Ras-induced senescence. Moreover, ΔNp73 cooperates with oncogenic Ras in transforming primary fibroblasts in vitro and in inducing MEF-derived fibrosarcomas in vivo in nude mice. Wild-type p53 is likely a major target of ΔNp73 inhibition in primary fibroblasts since deletion of p53 or its requisite upstream activator ARF abrogates the growth-promoting effect of ΔNp73. Taken together, ΔNp73 behaves as an oncogene that targets p53 that might explain why ΔNp73 upregulation may be selected for during tumorigenesis of human cancers.

Original languageEnglish (US)
Pages (from-to)5540-5555
Number of pages16
JournalMolecular and Cellular Biology
Volume23
Issue number16
DOIs
StatePublished - Aug 1 2003
Externally publishedYes

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Fibroblasts
Embryonic Structures
Up-Regulation
Apoptosis
Cultured Tumor Cells
Neoplasms
Fibrosarcoma
Cell Aging
Growth
Tumor Suppressor Genes
Oncogenes
Nude Mice
Transcriptional Activation
Protein Isoforms
Carcinogenesis
Cell Proliferation
Breast Neoplasms
Phenotype
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

ΔNp73 facilitates cell immortalization and cooperates with oncogenic Ras in cellular transformation in vivo. / Petrenko, Oleksi; Zaika, Alexander; Moll, Ute M.

In: Molecular and Cellular Biology, Vol. 23, No. 16, 01.08.2003, p. 5540-5555.

Research output: Contribution to journalArticle

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