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NORE1A Regulates MDM2 Via β-TrCP

Department of Pharmacology and Toxicology, James Graham Brown Cancer Center Molecular Targets Group, University of Louisville, Louisville, KY 40202, USA
Department of Clinical and Experimental Medicine, University of Sassari, Sassari 07100, Italy
Author to whom correspondence should be addressed.
Academic Editor: Reinhard Dammann
Cancers 2016, 8(4), 39;
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)
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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

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

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