Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation.

Abstract

UNLABELLED:

Hu antigen R (HuR) is a central RNA-binding protein regulating cell dedifferentiation, proliferation, and survival, which are well-established hallmarks of cancer. HuR is frequently overexpressed in tumors correlating with tumor malignancy, which is in line with a role for HuR in tumorigenesis. However, the precise mechanism leading to changes in HuR expression remains unclear. In the liver, HuR plays a crucial role in hepatocyte proliferation, differentiation, and transformation. Here, we unraveled a novel mean of regulation of HuR expression in hepatocellular carcinoma (HCC) and colon cancer. HuR levels correlate with the abundance of the oncogene, murine double minute 2 (Mdm2), in human HCC and colon cancer metastases. HuR is stabilized by Mdm2-mediated NEDDylation in at least three lysine residues, ensuring its nuclear localization and protection from degradation.

CONCLUSION:

This novel Mdm2/NEDD8/HuR regulatory framework is essential for the malignant transformation of tumor cells, which, in turn, unveils a novel signaling paradigm that is pharmacologically amenable for cancer therapy.

• Authors: Nieves Embade, David Fernández-Ramos, Marta Varela-Rey, Naiara Beraza, Marcella Sini, Virginia Gutiérrez de Juan, Ashwin Woodhoo, Nuria Martínez-López, Begoña Rodríguez-Iruretagoyena, Francisco Javier Bustamante, Ana Belén de la Hoz, Arkaitz Carracedo, Dimitris P Xirodimas, Manuel S Rodríguez, Shelly C Lu, José M Mato, María L Martínez-Chantar
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 55 Issue 4 Pg. 1237-48 (Apr 2012) ISSN: 1527-3350 [Electronic] United States
• PMID: 22095636 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American Association for the Study of Liver Diseases.

Chemical References

• ELAV Proteins
• NEDD8 Protein
• NEDD8 protein, human
• Nedd8 protein, mouse
• Ubiquitins
• MDM2 protein, human
• Mdm2 protein, mouse
• Proto-Oncogene Proteins c-mdm2

Topics

• Animals
• Carcinoma, Hepatocellular (metabolism, pathology)
• Case-Control Studies
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cell Transformation, Neoplastic (pathology)
• Colonic Neoplasms (metabolism, pathology)
• Cytoplasm (metabolism)
• Disease Models, Animal
• ELAV Proteins (metabolism)
• Hepatocytes (metabolism, pathology)
• Humans
• Liver Neoplasms (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• NEDD8 Protein
• Proto-Oncogene Proteins c-mdm2 (metabolism)
• Signal Transduction (physiology)
• Ubiquitins (metabolism)