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PMID: 12235210 Published · ppublish English Journal Article Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

DeltaNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors.

The Journal of experimental medicine ·Vol. 196 ·No. 6 ·2002-09-16 ·Pages 765-80

Zaika AI, Slade N, Erster SH, Sansome C, Joseph TW, Pearl M, Chalas E, Moll UM

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 NH(2) terminally truncated isoform. DeltaNp73 derives from an alternative promoter in intron 3 and lacks the transactivation domain of full-length TAp73. DeltaNp73 is frequently overexpressed in a variety of human cancers, but not in normal tissues. DeltaNp73 acts as a potent transdominant inhibitor of wild-type p53 and transactivation-competent TAp73. DeltaNp73 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 DeltaNp73 levels by antisense methods alleviates its suppressive action and enhances p53- and TAp73-mediated apoptosis. DeltaNp73 is complexed with wild-type p53, as demonstrated by coimmunoprecipitation from cultured cells and primary tumors. Thus, DeltaNp73 mediates a novel inactivation mechanism of p53 and TAp73 via a dominant-negative family network. Deregulated expression of DeltaNp73 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.

MeSH Terms
Animals Apoptosis Base Sequence DNA/metabolism DNA Damage DNA-Binding Proteins/antagonists & inhibitors,chemistry,genetics Drug Resistance, Neoplasm Gene Expression Regulation, Neoplastic Genes, Tumor Suppressor Humans Mice Molecular Sequence Data Mutation Nuclear Proteins/antagonists & inhibitors,chemistry,genetics Tumor Protein p73 Tumor Suppressor Protein p53/antagonists & inhibitors,chemistry Tumor Suppressor Proteins
Chemicals
DNA-Binding Proteins Nuclear Proteins TP73 protein, human Trp73 protein, mouse Tumor Protein p73 Tumor Suppressor Protein p53 Tumor Suppressor Proteins delta Np73 protein, human DNA
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Zaika Alex I
Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.
Slade Neda
Erster Susan H
Sansome Christine
Joseph Troy W
Pearl Michael
Chalas Eva
Moll Ute M
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20020179
Published
2002-09-16
Pages
765-80
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2194062
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20020179 PMC Full Text View journal details
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