Post-transcriptional regulation controlled by E-cadherin is important for c-Jun activity in melanoma.
A central event in the development of malignant melanoma is the loss of the tumor-suppressor protein E-cadherin. Here, we report that this loss is linked to the activation of the proto-oncogene c-Jun, a key player in tumorigenesis. In vivo, malignant melanomas show strong expression of the c-Jun protein in contrast to melanocytes. Interestingly, c-Jun mRNA levels did not differ in the melanoma cell lines when compared to melanocytes, suggesting that c-Jun could be regulated at the post-transcriptional level. To uncover the link between E-cadherin and c-Jun, we re-expressed E-cadherin in melanoma cells and detected decreased protein expression and activity of c-Jun. Furthermore, c-Jun accumulation is dependent on active E-cadherin-mediated cell-cell adhesion and regulated via the cytoskeleton. Additionally, we determined that, with respect to c-Jun regulation, there are two melanoma subgroups. One subgroup regulates c-Jun expression via the newly discovered E-cadherin-dependent signaling pathway, whereas the other subgroup uses the MAPKinases to regulate its expression. In summary, our data provide novel insights into the tumor-suppressor function of E-cadherin, which contributes to the suppression of c-Jun protein translation and transcriptional activity independent of MAPKinases.
Institute of Pathology, University of Regensburg, Regensburg, Germany.
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B
Spangler
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Vardimon
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Bosserhoff
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S
Kuphal
D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; D020928:Mitogen-Activated Protein Kinases