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Role of PIASy in the Regulation of Steroid Receptor Coactivator RAC3

by
Khanh G. Dinh
Master of Engineering, 2003
Nagoya University, Japan

Thesis Advisor: J. Don Chen, PhD
Graduate Program in Cellular & Molecular Pharmacology

RWJMS Research Tower
4th Floor Conference Room

Monday, August 24, 2009
2:00 pm


Abstract

Nuclear receptor (NR) has generally been defined as a family of transcription factors that bind to promoter of target genes and stimulate gene transcription in a ligand-dependent manner through the recruitment of coactivators such as the steroid receptor coactivators (SRC) family. The SRC/p160 family members comprise of SRC-1, SRC-2 and SRC-3/RAC3. RAC3 is the third member of SRC family that was previously identified by our lab. Despite the structural similarities and the common features of enhancing NR transactivation, members of SRC family have been shown to exhibit distant physiological functions. It was suggested that posttranslational protein modification may contribute to the differential activity of SRC-1, SRC-2 and SRC-3/RAC3. RAC3 protein is regulated by various posttranslational modifications such as ubiquitination, phosphorylation, methylation, acetylation or sumoylation. Sumoylation of SRC-1 and SRC-2 have been shown to either enhance the target NR-mediated gene transcription or to stabilize the formation of coactivator-NR complex. SUMO modification of RAC3, however, has been demonstrated to down-regulated the transcriptional activity of RAC3.
The PIAS family members, originally identified as negative regulators of STAT signaling, include PIAS1, PIAS3, PIASx (alpha and beta) and PIASy. PIAS family members have been shown to possess SUMO E3-ligase activity. In this study, we reported RAC3 as a novel target of PIASy. PIASy was found to directly interact with RAC3 and stimulate both sumoylation and neddylation of RAC3. Like sumoylation, neddylation also exerts a negative effect on RAC3 transcriptional activity. PIASy significantly inhibits RAC3 transcriptional activation function and the SP-RING motif of PIASy is essential for this repression. Stimulation of PIASy expression in breast cancer cells MCF-7 results in the attenuation of MCF-7 cell proliferation and a decreased transcriptional expression level of RAC3ís target genes that involve in breast carcinoma cell progression such as cyclin D1 and E2F1. Moreover, the reduced proliferative activity of MCF-7 cells due to the negative effect of PIASy on RAC3 was also found to correlate with an increased level of both sumoylation and neddylation of RAC3 proteins. Taken together, our observations suggest that RAC3 could be a potential target for transcriptional regulation mediated by PIASy, which could exert the repressive effect as a dual posttranslational protein modification E3-ligase.


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