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Distinct involvement of the Jun‐N‐terminal kinase and NF‐κB pathways in the repression of the human COL1A2 gene by TNF‐α
Author(s) -
Verrecchia Franck,
Wagner Erwin F.,
Mauviel Alain
Publication year - 2002
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1093/embo-reports/kvf219
Subject(s) - transactivation , psychological repression , kinase , biology , gene expression , signal transduction , microbiology and biotechnology , regulation of gene expression , iκb kinase , nfkb1 , transfection , gene , nf κb , genetics , transcription factor
We used a gene knockout approach to elucidate the specific roles played by the Jun‐N‐terminal kinase (JNK) and NF‐κB pathways downstream of TNF‐α in the context of α(2) type I collagen gene ( COL1A2 ) expression. In JNK 1 −/− ‐ JNK 2 −/− ( JNK −/− ) fibroblasts, TNF‐α inhibited basal COL1A2 expression but had no effect on TGF‐β‐driven gene transactivation unless jnk1 was introduced ectopically. Conversely, in NF‐κB essential modulator −/− ( NEMO −/− ) fibroblasts, lack of NF‐κB activation did not influence the antagonism exerted by TNF‐α against TGF‐β but prevented repression of basal COL1A2 gene expression. Similar regulatory mechanisms take place in dermal fibroblasts, as evidenced using transfected dominant‐negative forms of MKK4 and IKK‐α, critical kinases upstream of the JNK and NF‐κB pathways, respectively. These results represent the first demonstration of an alternate usage of distinct signaling pathways by TNF‐α to inhibit the expression of a given gene, COL1A2 , depending on its activation state.