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Molecular and Cellular Biology, December 2004, p. 10593-10610, Vol. 24, No. 24
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.24.10593-10610.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

PIAS-1 Is a Checkpoint Regulator Which Affects Exit from G1 and G2 by Sumoylation of p73

Eliana Munarriz,1 Daniela Barcaroli,1 Anastasis Stephanou,2 Paul A. Townsend,2 Carine Maisse,3 Alessandro Terrinoni,3 Michael H. Neale,1 Seamus J. Martin,4 David S. Latchman,2 Richard A. Knight,5 Gerry Melino,1,3 and Vincenzo De Laurenzi1,3*

Biochemistry Laboratory, IDI-IRCCS, c/o Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata," Rome, Italy,3 Toxicology Unit, Medical Research Council, Leicester University, Leicester,1 Medical Molecular Biology Unit, Institute of Child Health, University College London,2 Department of Cystic Fibrosis, National Heart and Lung Institute, London, United Kingdom,5 Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin, Ireland4

Received 26 March 2004/ Returned for modification 14 May 2004/ Accepted 23 September 2004

p73 is a recently described member of the p53 family, and, like p53, it undergoes a number of posttranslational modifications. Here we show, by yeast two-hybrid screening, pull-down assays, and coimmunoprecipitation, that p73{alpha}, -ß, and -{gamma} bind to the protein inhibitor of activated STAT-1 (PIAS-1) and that this binding stabilizes p73. PIAS-1 also sumoylates p73{alpha}, although not the C-terminally truncated isoforms p73ß and -{gamma}, and this requires the RING finger domain of PIAS-1. The {Delta}Np73{alpha} isoform can also bind, and be sumoylated by, PIAS-1. PIAS-1-mediated sumoylation decreases p73 transcriptional activity on several target promoters, such as Bax. p73 is colocalized in the nucleus with PIAS-1, and sumoylated p73 is located exclusively in the nuclear matrix. PIAS-1 is expressed predominantly during S phase, and PIAS-1 overexpression reduces p73-mediated transcription of p21, with a reduction of cells in G1 and cell cycle reentry. Inhibition of endogenous PIAS-1 by RNA interference reduces the proportion of cells in S phase and induces G2 arrest. These data suggest that PIAS-1, acting partly through binding and sumoylation of p73, is an important component of the cell cycle machinery.

* Corresponding author. Mailing address: Medical Research Council, Toxicology Unit, Hodgkin Building, Leicester University, Lancaster Rd., P.O. Box 138, Leicester LE1 9HN, United Kingdom. Phone: 44-116-2525564. Fax: 44-116-2525616. E-mail: vdl1{at}le.ac.uk.

Molecular and Cellular Biology, December 2004, p. 10593-10610, Vol. 24, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.24.10593-10610.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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