δNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors

Alexander Zaika, Neda Slade, Susan H. Erster, Christine Sansome, Troy W. Joseph, Michael Pearl, Eva Chalas, Ute M. Moll

Research output: Contribution to journalArticle

281 Citations (Scopus)

Abstract

p73 has significant homology to p53. However, tumor-associated up-regulation of p73 and genetic data from human tumors and p73-deficient mice exclude a classical Knudson-type tumor suppressor role. We report that the human TP73 gene generates an NH2 terminally truncated isoform. ΔNp73 derives from an alternative promoter in intron 3 and lacks the transactivation domain of full-length TAp73. ΔNp73 is frequently overexpressed in a variety of human cancers, but not in normal tissues. ΔNp73 acts as a potent transdominant inhibitor of wild-type p53 and transactivation-competent TAp73. ΔNp73 efficiently counteracts transactivation function, apoptosis, and growth suppression mediated by wild-type p53 and TAp73, and confers drug resistance to wild-type p53 harboring tumor cells. Conversely, down-regulation of endogenous ΔNp73 levels by antisense methods alleviates its suppressive action and enhances p53- and TAp73-mediated apoptosis. ΔNp73 is complexed with wild-type p53, as demonstrated by coimmunoprecipitation from cultured cells and primary tumors. Thus, ΔNp73 mediates a novel inactivation mechanism of p53 and TAp73 via a dominant-negative family network. Deregulated expression of ΔNp73 can bestow oncogenic activity upon the TP73 gene by functionally inactivating the suppressor action of p53 and TAp73. This trait might be selected for in human cancers.

Original languageEnglish (US)
Pages (from-to)765-780
Number of pages16
JournalJournal of Experimental Medicine
Volume196
Issue number6
DOIs
StatePublished - Sep 16 2002
Externally publishedYes

Fingerprint

Transcriptional Activation
Neoplasms
Apoptosis
Cultured Tumor Cells
Medical Genetics
Drug Resistance
Introns
Genes
Protein Isoforms
Up-Regulation
Down-Regulation
Growth

Keywords

  • ΔNp73
  • Apoptosis
  • Deregulation in tumor
  • Ex2Del p73
  • P73

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

δNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors. / Zaika, Alexander; Slade, Neda; Erster, Susan H.; Sansome, Christine; Joseph, Troy W.; Pearl, Michael; Chalas, Eva; Moll, Ute M.

In: Journal of Experimental Medicine, Vol. 196, No. 6, 16.09.2002, p. 765-780.

Research output: Contribution to journalArticle

Zaika, A, Slade, N, Erster, SH, Sansome, C, Joseph, TW, Pearl, M, Chalas, E & Moll, UM 2002, 'δNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors', Journal of Experimental Medicine, vol. 196, no. 6, pp. 765-780. https://doi.org/10.1084/jem.20020179
Zaika, Alexander ; Slade, Neda ; Erster, Susan H. ; Sansome, Christine ; Joseph, Troy W. ; Pearl, Michael ; Chalas, Eva ; Moll, Ute M. / δNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors. In: Journal of Experimental Medicine. 2002 ; Vol. 196, No. 6. pp. 765-780.
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AB - p73 has significant homology to p53. However, tumor-associated up-regulation of p73 and genetic data from human tumors and p73-deficient mice exclude a classical Knudson-type tumor suppressor role. We report that the human TP73 gene generates an NH2 terminally truncated isoform. ΔNp73 derives from an alternative promoter in intron 3 and lacks the transactivation domain of full-length TAp73. ΔNp73 is frequently overexpressed in a variety of human cancers, but not in normal tissues. ΔNp73 acts as a potent transdominant inhibitor of wild-type p53 and transactivation-competent TAp73. ΔNp73 efficiently counteracts transactivation function, apoptosis, and growth suppression mediated by wild-type p53 and TAp73, and confers drug resistance to wild-type p53 harboring tumor cells. Conversely, down-regulation of endogenous ΔNp73 levels by antisense methods alleviates its suppressive action and enhances p53- and TAp73-mediated apoptosis. ΔNp73 is complexed with wild-type p53, as demonstrated by coimmunoprecipitation from cultured cells and primary tumors. Thus, ΔNp73 mediates a novel inactivation mechanism of p53 and TAp73 via a dominant-negative family network. Deregulated expression of ΔNp73 can bestow oncogenic activity upon the TP73 gene by functionally inactivating the suppressor action of p53 and TAp73. This trait might be selected for in human cancers.

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