Wnt-5a mRNA translation is suppressed by the Elav-like protein HuR in human breast epithelial cells.
Wnt-5a is a non-transforming Wnt protein. Since Wnt-5a mRNA and protein levels differ within and between tumours, the potential of Wnt-5a as a prognostic factor has been debated. We have previously shown that the lack of Wnt-5a protein is a predictor of shorter disease-free survival in human breast cancer. Recently, however, we also showed that the breast tumours lacking Wnt-5a protein had a high or normal level of Wnt-5a mRNA that might explain the discrepancies in previous studies. We here report that Wnt-5a is regulated at the post-transcriptional level. The regulation was mediated by the Embryonic Lethal Abnormal Vision (ELAV)-like protein HuR, which inhibited translation of Wnt-5a when bound to highly conserved AU-rich sequences in the 3'-untranslated region (3'-UTR) of the Wnt-5a mRNA molecule, as shown by both HA-tagged Wnt-5a- and Luciferase-Wnt-5a-3'-UTR reporter assays. The HuR-dependent inhibition of Wnt-5a was supported by the fact that active HuR is located in the cytoplasm in invasive human breast tumours and that hypoxia-induced activation of HuR inhibits translation of both Luciferase-Wnt-5a-3'-UTR and endogenous Wnt-5a protein. We propose that the lack of Wnt-5a protein expression in invasive human breast tumours is caused by a HuR-mediated suppression of Wnt-5a mRNA translation.
Leandersson
Karin
K
Experimental Pathology, Lund University, Malmö, Sweden. Karin.Leandersson@med.lu.se
Riesbeck
Kristian
K
Andersson
Tommy
T
D020413:3' Untranslated Regions / Q000737:chemistry / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism*; D001483:Base Sequence; D001940:Breast / Q000166:cytology / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051153:Wnt Proteins / Q000096:biosynthesis / Q000235:genetics*; D000071818:Wnt-5a Protein
D020413:3' Untranslated Regions; D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein