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Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy

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Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy

Content Provider	Springer Nature Link
Author	Sane, Sanam Abdullah, Ammara Nelson, Morgan E. Wang, Hongmin Chauhan, Subhash C. Newton, Samuel S. Rezvani, Khosrow
Copyright Year	2015
Abstract	Overexpression of the oncoprotein mortalin in cancer cells and its protein partners enables mortalin to promote multiple oncogenic signaling pathways and effectively antagonize chemotherapy-induced cell death. A UBX-domain-containing protein, UBXN2A, acts as a potential mortalin inhibitor. This current study determines whether UBXN2A effectively binds to and occupies mortalin’s binding pocket, resulting in a direct improvement in the tumor’s sensitivity to chemotherapy. Molecular modeling of human mortalin’s binding pocket and its binding to the SEP domain of UBXN2A followed by yeast two-hybrid and His-tag pull-down assays revealed that three amino acids (PRO442, ILE558, and LYS555) within the substrate-binding domain of mortalin are crucial for UBXN2A binding to mortalin. As revealed by chase experiments in the presence of cycloheximide, overexpression of UBXN2A seems to interfere with the mortalin-CHIP E3 ubiquitin ligase and consequently suppresses the C‐terminus of the HSC70‐interacting protein (CHIP)-mediated destabilization of p53, resulting in its stabilization in the cytoplasm and upregulation in the nucleus. Overexpression of UBXN2A causes a significant inhibition of cell proliferation and the migration of colon cancer cells. We silenced UBXN2A in the human osteosarcoma U2OS cell line, an enriched mortalin cancer cell, followed by a clinical dosage of the chemotherapeutic agent 5-fluorouracil (5-FU). The UBXN2A knockout U2OS cells revealed that UBXNA is essential for the cytotoxic effect achieved by 5-FU. UBXN2A overexpression markedly increased the apoptotic response of U2OS cells to the 5-FU. In addition, silencing of UBXN2A protein suppresses apoptosis enhanced by UBXN2A overexpression in U2OS. The knowledge gained from this study provides insights into the mechanistic role of UBXN2A as a potent mortalin inhibitor and as a potential chemotherapy sensitizer for clinical application.
Starting Page	313
Ending Page	326
Page Count	14
File Format	PDF
ISSN	13558145
Journal	Cell Stress and Chaperones
Volume Number	21
Issue Number	2
e-ISSN	14661268
Language	English
Publisher	Springer Netherlands
Publisher Date	2015-12-04
Publisher Place	Dordrecht
Access Restriction	Subscribed
Subject Keyword	Mortalin UBXN2A p53 Chemotherapy Osteosarcoma Colon cancer Biomedicine general Cell Biology Biochemistry Immunology Cancer Research Neurosciences
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry

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Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy.

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Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy

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Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy