Abstract
Mortalin (mot-2) induces inactivation of the tumor suppressor p53's transcriptional and apoptotic functions by cytoplasmic sequestration of p53 in select cancers. The mot-2-dependent cytoprotective function enables cancer cells to support malignant transformation. Abrogating the p53-mot-2 interaction can control or slow down the growth of cancer cells. In this study, we report the discovery of a ubiquitin-like (UBX)-domain-containing protein, UBXN2A, which binds to mot-2 and consequently inhibits the binding between mot-2 and p53. Genetic analysis showed that UBXN2A binds to mot-2's substrate binding domain, and it partly overlaps p53's binding site indicating UBXN2A and p53 likely bind to mot-2 competitively. By binding to mot-2, UBXN2A releases p53 from cytosolic sequestration, rescuing the tumor suppressor functions of p53. Biochemical analysis and functional assays showed that the overexpression of UBXN2A and the functional consequences of unsequestered p53 trigger p53-dependent apoptosis. Cells expressing shRNA against UBXN2A showed the opposite effect of that seen with UBXN2A overexpression. The expression of UBXN2A and its apoptotic effects were not observed in normal colonic epithelial cells and p53−/− colon cancer cells. Finally, significant reduction in tumor volume in a xenograft mouse model in response to UBXN2A expression was verified in vivo. Our results introduce UBXN2A as a home defense response protein, which can reconstitute inactive p53-dependent apoptotic pathways. Inhibition of mot-2-p53 interaction by UBXN2A is an attractive therapeutic strategy in mot-2-elevated tumors.
Highlights
Mot-2 is a member of the heat-shock protein 70 family,[1] which increases in tumor cells
Cell shrinking, and alteration of nuclear morphology are ubiquitous aspects of apoptosis, we examined these apoptotic features in the presence of UBXN2A
On the basis of the cell morphology and reduced cell viability, it appeared that UBXN2A leads the cells to apoptosis, which was further confirmed by the large molecular weight DNA fragments in HCT-116 and LoVo colon cancer cells transiently transfected with GFP-UBXN2A or GFP-empty vector (Supplementary Figure 1B)
Summary
Mot-2 is a member of the heat-shock protein 70 family,[1] which increases in tumor cells. We show that the UBXN2A protein is a positive regulator of p53 through its interaction with the C-terminus of mot-2 where the p53-binding site is located. UBXN2A facilitates the translocation of WT-p53 to the nucleus where p53 regulates its target genes, those involved in apoptosis. These results introduce UBXN2A as an important anticancer factor that can contribute to p53 localization and activation as a host defense mechanism against cancerous growth. Because fully functional p53 can reverse tumor formation and progression as well as postpone tumor relapse,[11] characterization of mot-2’s endogenous regulators may lead to a new class of therapeutic interventions in tumors with high levels of mot-2
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
