The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/11/1763/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 9, November 2, 1998 1763-1768

Brief Definitive Reports

Two New p73 Splice Variants, {gamma} and {delta}, with Different Transcriptional Activity

Vincenzo De Laurenzi*, Antonio Costanzo{ddagger}, Daniela Barcaroli*, Alessandro Terrinoni*, Mirella Falco{ddagger}, Margherita Annicchiarico-Petruzzelli*, Massimo Levrero{ddagger}, and Gerry Melino*

From the * Biochemistry Laboratory, Istituto Dermopatico dell'Immacolata-IRCCS, Department of Experimental Medicine, University of Rome "Tor Vergata," 00133 Rome, Italy; and the {ddagger} Laboratory of Gene Expression, Fondazione Andrea Cesalpino, University of Rome "La Sapienza," 00161 Rome, Italy

p73 has been recently identified as a new structural and functional homologue of the transcription factor p53. It is expressed in either a full-length form, {alpha}, or a shorter β mRNA variant, with exon 13 spliced out. Here we report the identification and functional characterization of two new p73 splicing variants, {gamma} (splicing out exon 11) and {delta} (splicing out exons 11, 12, and 13). Both {gamma} and {delta} p73 variants are expressed in human peripheral blood lymphocytes, primary keratinocytes, and different tumor cell lines, including neuroblastoma, glioblastoma, melanoma, hepatoma, and leukemia. The expression pattern of the four p73 splicing variants differs in both primary cells of different lineage and established cell lines even within the same type of tumor. A two-hybrid assay was used to characterize the homodimeric and heterodimeric interactions between the p73 variants, and showed that neither p73{gamma} nor p73{delta} interact with p53, whereas p73{gamma} showed strong interactions with all p73 isoforms, and p73{delta} binds efficiently p73{alpha} and p73{gamma} but only weakly p73β. At the functional level, p73{gamma} is significantly less efficient in activating transcription of the p21Waf1/Cip1 promoter than p53 or p73β, whereas the effect of p73{delta} is intermediate and comparable to that of p73{alpha}. The ability of the different p73 variants to affect cell growth in p53 null osteosarcoma SAOS-2 cells correlates with their transcriptional activity on the p21Waf1/Cip1 promoter: p73β is the most efficient in inhibiting colony formation, whereas p73{gamma} is almost ineffective. Our results suggest that p73 isoforms may be differentially regulated, with four different isoforms capable of interacting among themselves and with p53. The relative expression level of each splice variant may modulate p73 transcriptional and growth suppression activities by affecting heterodimer formation.

Key Words: p73 • p53 • differentiation • apoptosis • cancer

Address correspondence to Gerry Melino, Biochemistry Laboratory, IDI-IRCCS, c/o Department of Experimental Medicine (F153/D26), University of Rome "Tor Vergata," via Tor Vergata 135, 00133 Rome, Italy. Phone: 39-6-20427299; Fax: 39-6-20427290; E-mail: gerry.melino{at}uniroma2.it


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