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Cancers 2016, 8(4), 39; doi:10.3390/cancers8040039

NORE1A Regulates MDM2 Via β-TrCP

1
Department of Pharmacology and Toxicology, James Graham Brown Cancer Center Molecular Targets Group, University of Louisville, Louisville, KY 40202, USA
2
Department of Clinical and Experimental Medicine, University of Sassari, Sassari 07100, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: Reinhard Dammann
Received: 14 January 2016 / Revised: 9 March 2016 / Accepted: 14 March 2016 / Published: 23 March 2016
(This article belongs to the Special Issue RASSF Signalling in Cancer)
View Full-Text   |   Download PDF [1896 KB, uploaded 23 March 2016]   |  

Abstract

Mouse Double Minute 2 Homolog (MDM2) is a key negative regulator of the master tumor suppressor p53. MDM2 regulates p53 on multiple levels, including acting as an ubiquitin ligase for the protein, thereby promoting its degradation by the proteasome. MDM2 is oncogenic and is frequently found to be over-expressed in human tumors, suggesting its dysregulation plays an important role in human cancers. We have recently found that the Ras effector and RASSF (Ras Association Domain Family) family member RASSF5/NORE1A enhances the levels of nuclear p53. We have also found that NORE1A (Novel Ras Effector 1A) binds the substrate recognition component of the SCF-ubiquitin ligase complex β-TrCP. Here, we now show that NORE1A regulates MDM2 protein levels by targeting it for ubiquitination by SCF-β-TrCP. We also show the suppression of NORE1A protein levels enhances MDM2 protein expression. Finally, we show that MDM2 can suppress the potent senescence phenotype induced by NORE1A over-expression. Thus, we identify a mechanism by which Ras/NORE1A can modulate p53 protein levels. As MDM2 has several important targets in addition to p53, this finding has broad implications for cancer biology in tumor cells that have lost expression of NORE1A due to promoter methylation. View Full-Text
Keywords: Ras; NORE1A; MDM2; β-TrCP Ras; NORE1A; MDM2; β-TrCP
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Schmidt, M.L.; Calvisi, D.F.; Clark, G.J. NORE1A Regulates MDM2 Via β-TrCP. Cancers 2016, 8, 39.

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