Open AccessTransactivation of Fra-1 and Consequent Activation of AP-1 Occur Extracellular Signal-Regulated Kinase Dependently
Author(s) -
Matthew R. Young,
Rajalakshmi Nair,
Natalie R. Bucheimer,
Preety Tulsian,
Nicole Brown,
Cristi Chapp,
Tin-Chen Hsu,
Nancy H. Colburn
Publication year - 2002
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.22.2.587-598.2002
Subject(s) - transactivation , mapk/erk pathway , biology , kinase , ap 1 transcription factor , transcription factor , microbiology and biotechnology , mitogen activated protein kinase , mitogen activated protein kinase 3 , protein kinase a , activator (genetics) , signal transduction , neoplastic transformation , cancer research , biochemistry , receptor , carcinogenesis , gene
Mitogen-activated protein (MAP) kinase, extracellular-signal-regulated kinases (ERKs) play an important role in activating AP-1-dependent transcription. Studies using the JB6 mouse epidermal model and a transgenic mouse model have established a requirement for AP-1-dependent transcription in tumor promotion. Tumor promoters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor induce activator protein 1 (AP-1) activity and neoplastic transformation in JB6 transformation-sensitive (P(+)) cells, but not in transformation-resistant (P(-)) variants. The resistance in one of the P(-) variants can be attributed to the low levels of the MAP kinases, ERKs 1 and 2, and consequent nonresponsiveness to AP-1 activation. The resistant variant is not deficient in c-fos transcription. The purpose of these studies was to define the targets of activated ERK that lead to AP-1 transactivation. The results establish that the transactivation domain of Fra-1 can be activated, that activation of Fra-1 is ERK dependent, and that a putative ERK phosphorylation site must be intact for activation to occur. Fra-1 was activated by TPA in ERK-sufficient P(+) cells but not in ERK-deficient P(-) cells. A similar activation pattern was seen for c-Fos but not for Fra-2. Gel shift analysis identified Fra-1 as distinguishing mitogen-activated (P(+)) from nonactivated (P(-)) AP-1 complexes. A second AP-1-nonresponsive P(-) variant that underexpresses Fra-1 gained AP-1 response upon introduction of a Fra-1 expression construct. These observations suggest that ERK-dependent activation of Fra-1 is required for AP-1 transactivation in JB6 cells.