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.
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.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA.
authors.forename: Zipeng
authors.initials: Z
authors.lastname: Cao
authors.forename: Ruowen
authors.initials: R
authors.lastname: Zhang
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.forename: Haishan
authors.initials: H
authors.lastname: Huang
authors.forename: Dongyun
authors.initials: D
authors.lastname: Zhang
authors.forename: Jingjie
authors.initials: J
authors.lastname: Zhang
authors.forename: Jimin
authors.initials: J
authors.lastname: Gao
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Chen
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002448:Cell Adhesion; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D019938:Cyclin D1; D014443:Tyrosine; D044767:Ubiquitin-Protein Ligases; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2
keywords: AP-1 Transcription Factor; Cyclin D1; E3 Ubiquitin Ligase; PP2A; XIAP