Loss of JunB activity enhances stromelysin 1 expression in a model of the epithelial-to-mesenchymal transition of mouse skin tumors.
Chemical carcinogenesis in mouse skin has been useful in delineating the molecular events that underlie squamous cell carcinoma progression. A late event in this progression, the epithelial-to-mesenchymal transition (EMT), is characterized by the loss of epithelial markers and the presence of mesenchymal markers. One mesenchymal marker associated with this transition is the matrix metalloproteinase stromelysin 1 (Str-1). To examine the molecular mechanisms regulating the expression of Str-1 during the EMT, genetically related mouse skin tumor cell lines representing the epithelial (B9(SQ)) and mesenchymal (A5(SP)) phenotypes were studied. As expected, B9(SQ) cells did not make Str-1, while A5(SP) cells did. B9(SQ)-A5(SP) somatic hybrids did not make Str-1, suggesting that a critical regulatory factor was a B9(SQ)-specific repressor. Str-1 promoter analysis revealed that a canonical AP-1 site was sufficient to maintain differential reporter gene activity. This result correlated with the observed loss of binding of the transcriptionally inactive JunB-Fra-2 AP-1 complex from B9(SQ) cells, being replaced primarily by the more active JunD-Fra-2 complex in A5(SP) cells. The higher level of JunB binding to both DNA and Fra-2 correlated with its hyperphosphorylation by Jun N-terminal kinase, an activity that was significantly higher in B9(SQ) cells. In the somatic hybrids, JunB gene expression was highly upregulated, a condition that also was sufficient to repress the expression of the endogenous Str-1 gene in A5(SP) cells. These data suggested that alterations in JunB activity, by changes in either phosphorylation or gene expression, contributed to the phenotypic differences that occur in this model of the EMT.
Hulboy
D L
DL
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2175, USA.
Matrisian
L M
LM
Crawford
H C
HC
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D003239:Connective Tissue Cells / Q000473:pathology* / Q000502:physiology*; D004847:Epithelial Cells / Q000473:pathology* / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D019278:Matrix Metalloproteinase 3 / Q000502:physiology*; D051379:Mice; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology
D016755:Proto-Oncogene Proteins c-jun; D019278:Matrix Metalloproteinase 3