title: Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation.
abstract: 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.
  
  
  CONCLUSIONS
  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.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Derio, Spain.
authors.forename: Nieves
authors.initials: N
authors.lastname: Embade
authors.forename: David
authors.initials: D
authors.lastname: Fernández-Ramos
authors.forename: Marta
authors.initials: M
authors.lastname: Varela-Rey
authors.forename: Naiara
authors.initials: N
authors.lastname: Beraza
authors.forename: Marcella
authors.initials: M
authors.lastname: Sini
authors.forename: Virginia
authors.initials: V
authors.lastname: Gutiérrez de Juan
authors.forename: Ashwin
authors.initials: A
authors.lastname: Woodhoo
authors.forename: Nuria
authors.initials: N
authors.lastname: Martínez-López
authors.forename: Begoña
authors.initials: B
authors.lastname: Rodríguez-Iruretagoyena
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Bustamante
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: de la Hoz
authors.forename: Arkaitz
authors.initials: A
authors.lastname: Carracedo
authors.forename: Dimitris P
authors.initials: DP
authors.lastname: Xirodimas
authors.forename: Manuel S
authors.initials: MS
authors.lastname: Rodríguez
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.forename: María L
authors.initials: ML
authors.lastname: Martínez-Chantar
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D051959:ELAV Proteins / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000075687:NEDD8 Protein; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D051959:ELAV Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; C513172:Nedd8 protein, mouse; D014452:Ubiquitins; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2
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