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: Honglei Jin, Jiheng Xu, Xirui Guo, Haishan Huang, Jingxia Li, Minggang Peng, Junlan Zhu, Zhongxian Tian, Xue-Ru Wu, Moon-Shong Tang, Chuanshu Huang
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 35 Pg. 56540-56557 (Aug 30 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27447744 (Publication Type: Journal Article)

Chemical References

• MIRN4295 microRNA, human
• MicroRNAs
• Sp1 Transcription Factor
• TP63 protein, human
• Transcription Factors
• Tumor Suppressor Proteins
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• Epidermal Growth Factor
• Methionine

Topics

• Animals
• Apoptosis (drug effects)
• Carcinogenesis
• Cell Adhesion
• Cell Proliferation
• Cell Transformation, Neoplastic
• Epidermal Growth Factor (metabolism)
• Epithelial Cells (cytology)
• Gene Expression Regulation, Neoplastic
• Humans
• Methionine (chemistry)
• Mice
• Mice, Transgenic
• MicroRNAs (genetics, metabolism)
• Protein Biosynthesis
• Protein Domains
• Sp1 Transcription Factor (metabolism)
• Transcription Factors (metabolism)
• Tumor Suppressor Proteins (metabolism)
• Up-Regulation
• Urinary Bladder (cytology)
• Urinary Bladder Neoplasms (genetics, metabolism)
• X-Linked Inhibitor of Apoptosis Protein (metabolism)