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Molecular and Cellular Biology, June 2003, p. 4401-4415, Vol. 23, No. 12
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.12.4401-4415.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Accumulation of Fra-1 in ras-Transformed Cells Depends on Both Transcriptional Autoregulation and MEK-Dependent Posttranslational Stabilization

Laura Casalino, Dario De Cesare, and Pasquale Verde*

Institute of Genetics and Biophysics "A. Buzzati-Traverso," Consiglio Nazionale delle Ricerche, 80125 Naples, Italy

Received 14 October 2002/ Returned for modification 19 December 2002/ Accepted 20 March 2003

The AP-1 transcription factor plays an essential role in cell proliferation and tumorigenesis. It was previously shown that the fra-1 gene product is upregulated by various oncogenes and is involved in the in vitro and in vivo transformation of thyroid cells. Here we show that the ras oncogene-dependent accumulation of Fra-1 is mediated by a positive feedback mechanism which requires both transcriptional autoregulation and posttranslational stabilization of the protein. The oncogene-dependent transcriptional activation involves the cooperation between both Raf-dependent and Raf-independent pathways and is mediated by an AP-1 site within the fra-1 first intron, which becomes stably occupied by a transcriptionally active Fra-1-containing complex in ras-transformed cells. The posttranslational stabilization results in a drastic increase in the Fra-1 half-life in ras-transformed cells and is totally dependent on the activity of the MEK/ERK phosphorylation pathway. The analysis of the Fra-1 transactivation potential shows that the protein is able to stimulate a heterologous promoter in a ras-dependent manner, but the transactivating activity requires the recruitment of a heterodimeric partner. These data show that the alteration of multiple regulatory mechanisms is required for the constitutive activation of Fra-1 as a nuclear target of ras transformation.

* Corresponding author. Mailing address: Institute of Genetics and Biophysics "A. Buzzati-Traverso," CNR, 80125 Naples, Italy. Phone: 39 081 7257 256. Fax: 39 081 593 7173. E-mail: verde{at}iigb.na.cnr.it.

Molecular and Cellular Biology, June 2003, p. 4401-4415, Vol. 23, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.12.4401-4415.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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