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

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.
Mesh Terms:
Animals, Carcinoma, Hepatocellular, Case-Control Studies, Cell Line, Tumor, Cell Nucleus, Cell Transformation, Neoplastic, Colonic Neoplasms, Cytoplasm, Disease Models, Animal, Hepatocytes, Hu Paraneoplastic Encephalomyelitis Antigens, Humans, Liver Neoplasms, Male, Mice, Mice, Inbred C57BL, Proto-Oncogene Proteins c-mdm2, Signal Transduction, Ubiquitins
Hepatology
Date: Apr. 01, 2012
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