title: XIAP RING domain mediates miR-4295 expression and subsequently inhibiting p63α protein translation and promoting transformation of bladder epithelial cells.
abstract: The X-linked inhibitor of apoptosis protein (XIAP) contains three N-terminal BIR domains that mediate anti-apoptosis and one C-terminal RING finger domain whose function(s) are not fully defined. Here we show that the RING domain of XIAP strongly inhibits the expression of p63α, a known tumor suppressor. XIAP knockdown in urothelial cells or RING deletion in knockin mice markedly upregulates p63α expression. This RING-mediated p63α downregulation is critical for the malignant transformation of normal urothelial cells following EGF treatment. We further show that the RING domain promotes Sp1-mediated transcription of miR-4295 which targets the 3'UTR of p63α mRNA and consequently inhibits p63α translation. Our results reveal a previously unknown function of the RING of XIAP in promoting miR-4295 transcription, thereby reducing p63α translation and enhancing urothelial transformation. Our data offer novel insights into the multifunctional effects of the XIAP RING domain on urothelial tumorigenesis and the potential for targeting this frequently overexpressed protein as a therapeutic alternative.
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.|Nelson Institute of Environmental Medicine, New York University, School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Honglei
authors.initials: H
authors.lastname: Jin
authors.affiliation: Nelson Institute of Environmental Medicine, New York University, School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Jiheng
authors.initials: J
authors.lastname: Xu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University, School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Xirui
authors.initials: X
authors.lastname: Guo
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Haishan
authors.initials: H
authors.lastname: Huang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University, School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.affiliation: Nelson Institute of Environmental Medicine, New York University, School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Minggang
authors.initials: M
authors.lastname: Peng
authors.affiliation: Nelson Institute of Environmental Medicine, New York University, School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Junlan
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University, School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Zhongxian
authors.initials: Z
authors.lastname: Tian
authors.affiliation: Department of Urology, New York University School of Medicine, New York, NY 10016, USA.|Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.|VA Medical Center in Manhattan, New York, NY 10010, USA.
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.affiliation: Nelson Institute of Environmental Medicine, New York University, School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Moon-Shong
authors.initials: MS
authors.lastname: Tang
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.|Nelson Institute of Environmental Medicine, New York University, School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis; D002448:Cell Adhesion; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008715:Methionine / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D000072417:Protein Domains; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation; D001743:Urinary Bladder / Q000166:cytology*; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: C000602903:MIRN4295 microRNA, human; D035683:MicroRNAs; D016329:Sp1 Transcription Factor; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D004815:Epidermal Growth Factor; D008715:Methionine
keywords: RING domain; XIAP; bladder cancer transformation; p63α