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Molecular and Cellular Biology, December 1999, p. 8052-8065, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Novel Membrane-Targeted ERK1 and ERK2 Chimeras Which Act as Dominant Negative, Isotype-Specific Mitogen-Activated Protein Kinase Inhibitors of Ras-Raf-Mediated Transcriptional Activation of c-fos in NIH 3T3 Cells

Franz Hochholdinger,1 Gottfried Baier,2 Anto Nogalo,1 Birgit Bauer,2 Hans H. Grunicke,1 and Florian Überall1,*

Institute of Medical Chemistry and Biochemistry1 and Institute of Medical Biology and Human Genetics,2 University of Innsbruck, A-6020 Innsbruck, Austria

Received 24 May 1999/Returned for modification 6 July 1999/Accepted 8 September 1999

Expression of constructs encoding fusion proteins of ERK1 and ERK2 containing a C-terminal farnesylation motif (CAAX) is predominantly localized at the cell membrane and was activated by coexpression of constitutively active Ha-RasL61 and epidermal growth factor. Both fusion proteins significantly inhibit the transcriptional activation of a c-fos-chloramphenicol acetyltransferase reporter induced by RasL61, constitutively active MEK1, or constitutively active RafBXB. The corresponding SAAX chimeras or overexpression of the wild-type ERKs did not interfere with the transcriptional activation of c-fos. The inhibition of the Ras-mediated c-fos induction by ERK2-CAAX can in part be rescued by coexpression of a wild-type ERK2 but not by wild-type ERK1. We find that ERK1-CAAX acts in the same fashion, indicating that mitogen-activated protein kinase (MAPK)-CAAX chimeras interact in an isotype-specific manner. It is demonstrated that both ERK1-CAAX and ERK2-CAAX associate with the corresponding endogenous ERKs, which explains the isotype-specific inhibitory effects of the ERK-CAAX chimeras. Evidence is presented that expression of ERK-CAAX fusion proteins inhibits the nuclear translocation of the corresponding endogenous ERKs. Disruption of MAPK translocation by membrane targeting provides additional, independent proof that nuclear translocation of ERKs is essential for the transcriptional activation of c-fos.

* Corresponding author. Mailing address: Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Fritz Preglstr. 3, A-6020 Innsbruck, Austria. Phone: 43-512-507-3508. Fax: 43-512-507-2872. E-mail: Florian.Ueberall{at}uibk.ac.at.

Molecular and Cellular Biology, December 1999, p. 8052-8065, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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