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(Circulation Research. 2003;92:1201.)
© 2003 American Heart Association, Inc.

Molecular Medicine

Modification of GATA-2 Transcriptional Activity in Endothelial Cells by the SUMO E3 Ligase PIASy

Tae-Hwa Chun, Hiroshi Itoh, Lalitha Subramanian, Jorge A. Iñiguez-Lluhí, Kazuwa Nakao

From the Department of Medicine and Clinical Science (T.C., H.I., K.N.), Kyoto University Graduate School of Medicine, Kyoto, Japan, and Departments of Pharmacology (L.S., J.I.) and Internal Medicine (T.C., S.W.), University of Michigan Medical Center, Ann Arbor, Mich.

Correspondence to Tae-Hwa Chun, 5240 MSRBIII, 1150 W Medical Center Dr, Ann Arbor, MI 48109. E-mail taehwa{at}umich.edu

GATA sequences are required for the optimal expression of endothelial cell–specific genes, including endothelin-1 (ET-1). We have identified PIASy in a search for new GATA-2 interacting proteins that can regulate GATA-2–mediated endothelial gene expression. Notably, among the cell populations comprising vascular walls, PIASy mRNA is selectively expressed in endothelial cells, and its expression can be regulated by angiogenic growth factors. We show that GATA-2 is covalently modified by small ubiquitin-like modifier (SUMO)-1 and -2 and that PIASy, through its E3 SUMO ligase activity, preferentially enhances the conjugation of SUMO-2 to GATA-2. Through a functional analysis, we demonstrate that PIASy potently suppresses the activity of the GATA-2–dependent human ET-1 promoter in endothelial cells. The suppressive effect of PIASy requires the GATA-binding site in the ET-1 promoter and depends on its interaction with GATA-2, which requires both N-terminal (amino acids 1-183) and C-terminal (amino acids 414-510) sequences in PIASy. We conclude that PIASy enhances the conjugation of SUMO-2 to GATA-2 and that the interaction of PIASy with GATA-2 can modulate GATA-mediated ET-1 transcription activity in endothelial cells through a RING-like domain-independent mechanism.

Key Words: GATA-2 • endothelin-1 • SUMO ligase • PIAS family

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