Abstract: The work presented in this thesis is aimed at providing insight into the role of PIAS proteins. The PIAS family of proteins consists of four members: PIAS1, PIAS3, PIASx, and PIASy. PIAS proteins were initially identified in a screen for proteins that interact with the transcription factor STAT. Thus the ability of PIAS proteins to function as transcriptional regulators is the primary focus of this work. The PIAS family is highly conserved, and our initial studies addressed the identification and function of specific domains of PIAS proteins. In the case of androgen receptor signaling, we show that PIASy interacts with androgen receptor (AR). Contrary to other family members, we show PIASy inhibits transcriptional activation by AR. Our studies indicate that the mechanism of PIASy repression is due to its ability to interact with other co-repressors such as HDAC. We also examined the importance of the conserved domains by deletional analysis, identifying two distinct repression domains with a critical LXXLL motif in AR signaling, and demonstrating the ability of the Ring-finger like domain to mediate interaction with AR. Subsequently, we examined the role of PIAS in NF-κB signaling. We show that while PIAS1 acts as a repressor, PIASx is a positive regulator of NF-κB. Genetic studies reveal that the mechanism of PIAS regulation of NF-κB is at the level of DNA binding. NF-κB binding is increased in the absence of PIAS1 but decreased in the absence of PIASx. Regulation is also gene specific, where a non-overlapping subset of NF-κB target genes is affected in PIAS1 deficient or PIASx knockdown cells. The activities of PIAS on NF-κB regulation are dependent on a phosphorylation event on the amino-terminus of PIAS which occurs upon cytokine stimulation.