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v‐src activation of the collagenase‐1 (matrix metalloproteinase‐1) promoter through PEA3 and STAT: Requirement of extracellular signal‐regulated kinases and inhibition by retinoic acid receptors
Author(s) -
Vincenti Matthew P.,
Schroen Daniel J.,
Coon Charles I.,
Brinckerhoff Constance E.
Publication year - 1998
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/(sici)1098-2744(199803)21:3<194::aid-mc7>3.0.co;2-m
Subject(s) - biology , proto oncogene tyrosine protein kinase src , microbiology and biotechnology , retinoic acid receptor , retinoic acid , stat protein , signal transduction , biochemistry , stat3 , gene
Collagenase‐1 (matrix metalloproteinase‐1 (MMP‐1)) degrades the extracellular matrix and enhances the invasive phenotype of tumor cells. v‐src activated MMP‐1 transcription through a series of elements in the proximal promoter, including the E2BP (nt‐172), polyoma virus enhancer A3 (PEA3) (nt‐94), activator protein‐1 (AP‐1) (nt‐72), and signal transducer and activator of transcription (STAT) (nt‐57) consensus sites. Of these sites, PEA3 and STAT contributed specifically to induction by v‐src, whereas the remaining elements were also involved in induction by the phorbol ester phorbol myristate acetate (PMA). However, in contrast to MMP‐1 induction by PMA, an AP‐1 site located at nt‐186 did not contribute to v‐src induction. These results suggest divergence of the tyrosine kinase– and protein kinase C–dependent pathways with respect to MMP‐1 transcription. v‐src induced MMP‐1 through mitogen‐activated protein kinases, with extracellular signal–regulated kinases playing a larger role than c‐jun N‐terminal kinase. Retinoic acid, which inhibits the progression of certain cancers, repressed v‐src–induced MMP‐1 transcription. Constitutive expression of retinoic acid receptors (RARs) α or β, but not γ, or of retinoid X receptor α, repressed v‐src–induced collagenase‐1 transcription. We concluded that oncogenic induction of MMP‐1 by v‐src depends on signaling pathways and cis‐acting sequences that are distinct from those involved in phorbol ester activation. Furthermore, v‐src induction of MMP‐1 may, by acting in concert with other genes, enhance matrix degradation and tumor progression, and retinoic acid and RARs may antagonize this induction in an RAR type–specific manner. Mol. Carcinog. 21:194–204, 1998. © 1998 Wiley‐Liss, Inc.