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Molecular and Cellular Biology, January 2002, p. 587-598, Vol. 22, No. 2
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.2.587-598.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Transactivation of Fra-1 and Consequent Activation of AP-1 Occur Extracellular Signal-Regulated Kinase Dependently

Matthew R. Young,1* Rajalakshmi Nair,1 Natalie Bucheimer,1 Preety Tulsian,1 Nicole Brown,1 Cristi Chapp,1 Tin-Chen Hsu,2 and Nancy H. Colburn1

Basic Research Laboratory, National Cancer Institute—Frederick,1 Intramural Research Support Program, Science Applications International Corporation—Frederick, Frederick, Maryland 217022

Received 9 July 2001/ Returned for modification 7 August 2001/ Accepted 10 October 2001

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.

* Corresponding author. Mailing address: Basic Research Laboratory, National Cancer Institute—Frederick, P.O. Box B, Bldg. 560, Rm. 21-27, Frederick, MD 21702. Phone: (301) 846-1333. Fax: (301) 846-6143. E-mail:youngm{at}ncifcrf.gov.

Molecular and Cellular Biology, January 2002, p. 587-598, Vol. 22, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.2.587-598.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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