Naslov
Delta Np73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors

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

Izvornik
The Journal of experimental medicine (0022-1007) 196 (2002), 6; 765-780

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
p73 ; delta Np73 ; Ex2Del p73 ; apoptosis ; deregulation in tumor

Sažetak
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 terminally truncated isoform. Delta Np73 derives from an alternative promoter in intron 3 and lacks the transactivation domain of full-length TAp73. Delta Np73 is frequently overexpressed in a variety of human cancers, but not in normal tissues. Delta Np73 acts as a potent transdominant inhibitor of wild-type p53 and transactivation-competent TAp73. Delta Np73 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 delta Np73 levels by antisense methods alleviates its suppressive action and enhances p53- and TAp73-mediated apoptosis. Delta Np73 is complexed with wild-type p53, as demonstrated by coimmunoprecipitation from cultured cells and primary tumors. Thus, delta Np73 mediates a novel inactivation mechanism of p53 and TAp73 via a dominant-negative family network. Deregulated expression of delta Np73 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.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti, Kliničke medicinske znanosti

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