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J. Biol. Chem., Vol. 279, Issue 34, 36121-36131, August 20, 2004

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Repression of the Transactivating Capacity of the Oncoprotein PLAG1 by SUMOylation^*

Frederik Van Dyck, Els L. D. Delvaux, Wim J. M. Van de Ven, and Marcela V. Chavez

From the Laboratory for Molecular Oncology, Department for Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, Herestraat 49, B-3000 Leuven, Belgium

Human pleomorphic adenoma gene 1 (PLAG1), a developmentally regulated proto-oncogene, is consistently rearranged and overexpressed in pleomorphic salivary gland adenomas and lipoblastomas with 8q12 translocations. Together with PLAGL1 and PLAGL2, PLAG1 belongs to a subfamily of C₂H₂ zinc finger transcription factors that activate transcription through binding to the bipartite consensus sequence GRGGC(N)_6–8GGG. Ectopic expression of PLAG1 deregulates target genes and presumably results in uncontrolled cell proliferation. To gain insight into molecular mechanisms regulating PLAG transcriptional capacity, we searched for interaction partners using the yeast two-hybrid system and confirmed these by glutathione S-transferase pull-down. Ubiquitin-conjugating enzyme 9 (UBC9) and protein inhibitor of activated STAT (PIAS) proteins were first identified as genuine interacting partners of mouse PlagL2. Because UBC9 and PIAS are components of the small ubiquitin-related modifier (SUMO) modification pathway, we hypothesized that PLAG proteins could be SUMOylated. Here, we report results obtained for founding family member PLAG1. Its endogenous SUMOylation was demonstrated, and SUMOylation of PLAG1 was further investigated in cells co-transfected with PLAG1 and SUMO-1 DNA or a SUMO-1 mutant form and similarly examined in the presence or absence of DNA encoding the various PIAS proteins. Using anti-PLAG1 antibodies, we discovered single and double SUMO-1-modified forms of PLAG1. By mutating predicted SUMO consensus sites, we defined two important target lysines for SUMOylation in PLAG1, Lys-244 and Lys-263. Moreover, mutation of both SUMO consensus sequences, resulting in inhibition of SUMOylation, led to a significant increase of the transactivation capacity of PLAG1. Nuclear distribution of PLAG1 was not measurably influenced. Our results suggest a direct repression of the transactivating capacity of the oncoprotein PLAG1 by SUMOylation.

Received for publication, February 17, 2004 , and in revised form, June 9, 2004.

^* This work was sponsored in part by Geconcerteerde Onderzoeksacties Grant 2002/10 and by grants from the Cancer Research Program of "Fortis Verzekeringen," from the "Fonds voor Wetenschappelijk Onderzoek, Vlaanderen" (Grant G.0099.02), and by the Belgian Federation against Cancer (Grant A5890). 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.

Awarded a bursary by the "Instituut voor de Aanmoediging van Innovatie door Wetenschap en Technologie in Vlaanderen."

To whom correspondence should be addressed. Tel.: 32-16-346080; Fax: 32-16-346073; E-mail: wim.vandeven{at}med.kuleuven.ac.be.

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