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J. Biol. Chem., Vol. 280, Issue 28, 26517-26525, July 15, 2005

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A Novel Peroxisome Proliferator-activated Receptor Isoform with Dominant Negative Activity Generated by Alternative Splicing^*

Lina Sabatino¶, Amelia Casamassimi¶||, Gianfranco Peluso**, Maria Vittoria Barone**, Daniela Capaccio, Chiara Migliore||, Patrizia Bonelli**, Antonio Pedicini, Antonio Febbraro, Alfredo Ciccodicola||¶¶, and Vittorio Colantuoni||||

From the Department of Biological and Environmental Sciences, University of Sannio, Via Port'Arsa 11, 82100 Benevento, the Department of Biochemistry and Medical Biotechnologies and Pediatric Department (ELFID), University of Naples Federico II, Via Pansini 5 80131 Naples, the ^||Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," (IGB), Consiglio Nazionale delle Ricerche, Via Castellino 111, 80131 Naples, the ^**Department of Experimental Oncology, National Cancer Institute "Fondazione G. Pascale," Via Semmola, 80131 Naples, and the Division of Medical Oncology, Fatebenefratelli Hospital, Viale Principe di Napoli, 82100 Benevento, Italy

We examined the peroxisome proliferator-activated receptor (PPARG) locus in an attempt to identify expressed sequence tags and/or conserved non-coding sequences in the intron sequences containing open reading frames and potentially able to encode new proteins. We identified a new PPARG transcript, defined ORF4, which harbors a readthrough in intron 4. The expected translated protein lacks the ligand-binding domain encoded by exons 5 and 6. We identified the transcript in human tumor cell lines and tissues, synthesized the cDNA, and cloned it in expression vectors. Using transient transfections, we found that ORF4 cDNA is translated into a predominantly nuclear protein that does not transactivate a reporter gene. Moreover, the isoform is dominant negative versus PPAR. Interestingly, ORF4 was expressed in vivo in a series of sporadic colorectal cancers. In some cases, it was expressed, albeit at lower levels, also in the mucosa adjacent to the tumors, suggesting that it may be related to tumorigenesis. A tumorigenic effect of ORF4 is in line with our finding that ORF4 has not only lost the capacity to restrain cell growth but has acquired the potential to stimulate it. In conclusion, this study demonstrates that ORF4 is expressed in vivo, that it has lost some PPAR properties, and that it affects PPAR functioning. The ability to counteract PPAR suggests that ORF4 plays a role in the pathogenesis of colorectal cancers.

Received for publication, March 11, 2005

^* This work was supported by Grants PRIN 2002 and FIRB 2001 from MIUR, the Associazione Italiana per la Ricerca sul Cancro (to V. C.) and by grants from the Italian Ministry of Health "Programmi speciali-Progetti Finalizzati 2003" (to G. P., A. C. and V. C.) and Telethon-Italy (to A. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Both authors contributed equally to this work.

^¶¶ To whom correspondence may be addressed. Tel.: 39-0824-305100; Fax: 39-0824-23013; E-mail: colantuoni{at}unisannio.it.

^|||| To whom correspondence may be addressed. Tel.: 39-081-6132259; Fax 39-081-6132258; E-mail: ciccodic{at}igb.cnr.it.

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