Title: X-linked inhibitor of apoptosis protein (XIAP) regulation of cyclin D1 protein expression and cancer cell anchorage-independent growth via its E3 ligase-mediated protein phosphatase 2A/c-Jun axis.
Authors: Cao, Zipeng; Zhang, Ruowen; Li, Jingxia; Huang, Haishan; Zhang, Dongyun; Zhang, Jingjie; Gao, Jimin; Chen, Jingyuan; Huang, Chuanshu
Published In J Biol Chem, (2013 Jul 12)
Abstract: The X-linked inhibitor of apoptosis protein (XIAP) is a well known potent inhibitor of apoptosis; however, it is also involved in other cancer cell biological behavior. In the current study, we discovered that XIAP and its E3 ligase played a crucial role in regulation of cyclin D1 expression in cancer cells. We found that deficiency of XIAP expression resulted in a marked reduction in cyclin D1 expression. Consistently, cell cycle transition and anchorage-independent cell growth were also attenuated in XIAP-deficient cancer cells compared with those of the parental wild-type cells. Subsequent studies demonstrated that E3 ligase activity within the RING domain of XIAP is crucial for its ability to regulate cyclin D1 transcription, cell cycle transition, and anchorage-independent cell growth by up-regulating transactivation of c-Jun/AP-1. Moreover, we found that E3 ligase within RING domain was required for XIAP inhibition of phosphatase PP2A activity by up-regulation of PP2A phosphorylation at Tyr-307 in its catalytic subunit. Such PP2A phosphorylation and inactivation resulted in phosphorylation and activation of its downstream target c-Jun in turn leading to cyclin D1 expression. Collectively, our studies uncovered a novel function of E3 ligase activity of XIAP in the up-regulation of cyclin D1 expression, providing significant insight into the understanding of the biomedical significance of overexpressed XIAP in cancer development, further offering a new molecular basis for utilizing XIAP E3 ligase as a cancer therapeutic target.
PubMed ID: 23720779
MeSH Terms: Binding Sites/genetics; Blotting, Western; Cell Adhesion; Cell Proliferation*; Colonic Neoplasms/genetics; Colonic Neoplasms/metabolism; Colonic Neoplasms/pathology; Cyclin D1/genetics; Cyclin D1/metabolism*; G1 Phase; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Mutation; Phosphorylation; Protein Phosphatase 2/genetics; Protein Phosphatase 2/metabolism*; Proto-Oncogene Proteins c-jun/genetics; Proto-Oncogene Proteins c-jun/metabolism*; RNA Interference; Reverse Transcriptase Polymerase Chain Reaction; S Phase; Transcription Factor AP-1/genetics; Transcription Factor AP-1/metabolism; Tyrosine/genetics; Tyrosine/metabolism; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism*; X-Linked Inhibitor of Apoptosis Protein/genetics; X-Linked Inhibitor of Apoptosis Protein/metabolism*