The Journal of Experimental Medicine
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Published 16 September 2002. doi:10.1084/jem.20020179
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© Rockefeller University Press, 0022-1007/2002/9/765/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 6, September 16, 2002 765-780
{Delta}Np73, A Dominant-Negative Inhibitor of Wild-type p53 and TAp73, Is Up-regulated in Human Tumors

Alex I. Zaika1, Neda Slade1, Susan H. Erster1, Christine Sansome1, Troy W. Joseph1, Michael Pearl2, Eva Chalas2 and Ute M. Moll1

1 Department of Pathology, Stony Brook University, Stony Brook, NY 11794
2 Department of Obstetrics and Gynecology, Stony Brook University, Stony Brook, NY 11794

Address correspondence to Ute M. Moll, Department of Pathology, BST L9 R134, Stony Brook University, Stony Brook, NY 11794. Phone: 631-444-2459; Fax: 631-444-3424; E-mail: umoll{at}notes.cc.sunysb.edu

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. {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.

Key Words: p73 • {Delta}Np73 • Ex2Del p73 • apoptosis • deregulation in tumor


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