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J. Biol. Chem., Vol. 281, Issue 30, 20940-20948, July 28, 2006

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DJ-1 Transcriptionally Up-regulates the Human Tyrosine Hydroxylase by Inhibiting the Sumoylation of Pyrimidine Tract-binding Protein-associated Splicing Factor^*

Nan Zhong, Christina Y. Kim, Patrizia Rizzu, Changiz Geula^¶, Douglas R. Porter^||, Emmanuel N. Pothos^||1, Ferdinando Squitieri^**, Peter Heutink², and Jin Xu³

From the Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston 02135, Massachusetts, the Department of Human Genetics, Vrise University (VU) University Medical Center and VU University, Amsterdam, The Netherlands, the ^¶Laboratory for Neurodegenerative and Aging Research, Department of Medicine, Harvard Medical School and Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, the ^||Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111, and the ^**Neurogenetics Unit, IRCCS Neuromed, 86077 Pozzilli, Italy

Loss-of-function mutations in DJ-1 cause a subset of familial Parkinson disease (PD). However, the mechanism underlying the selective vulnerability in dopaminergic pathway due to the inactivation of DJ-1 is unclear. Previously, we have reported that DJ-1 is a neuroprotective transcriptional co-activator interacting with the transcriptional co-repressor pyrimidine tract-binding protein-associated splicing factor (PSF). Here we show that DJ-1 and PSF bind and regulate the human tyrosine hydroxylase (TH) promoter. Inactivation of DJ-1 by small interference RNA (siRNA) results in decreased TH expression and L-DOPA production in human dopaminergic cell lines. Consistent with its role as a transcriptional regulator, DJ-1 specifically suppresses the global SUMO-1 modification. High molecular weight sumoylated protein species, including PSF, accumulate in the lymphoblast cells from the patients carrying pathogenic DJ-1 mutations. DJ-1 elevates the TH expression by inhibiting the sumoylation of PSF and preventing its sumoylation-dependent recruitment of histone deacetylase 1. Furthermore, siRNA silencing of DJ-1 decreases the acetylation of TH promoter-bound histones, and histone deacetylase inhibitors restore the DJ-1 siRNA-induced repression of TH. Therefore, our results suggest DJ-1 as a regulator of protein sumoylation and directly link the loss of DJ-1 expression and transcriptional dysfunction to impaired dopamine synthesis.

Received for publication, February 28, 2006 , and in revised form, May 18, 2006.

^* This work was supported in part by research grants from the American Parkinson's Disease Association and Parkinson's Disease Foundation (to J. X.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported by research grants from the American Parkinson's Disease Association and Parkinson's Disease Foundation.

² Supported by the Michael J. Fox Foundation.

³ To whom correspondence should be addressed: Dept. of Neurology, Caritas St. Elizabeth's Medical Center, 736 Cambridge St., CBR4, Boston, MA 02135. Tel.: 617-789-2935; Fax: 617-789-3111; E-mail: Jin.Xu{at}tufts.edu.

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