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Molecular and Cellular Biology, October 2008, p. 6483-6495, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00288-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Epidermal Growth Factor Receptor 1 (EGFR1) and Its Variant EGFRvIII Regulate TATA-Binding Protein Expression through Distinct Pathways{triangledown}

Jody A. Fromm, Sandra A. S. Johnson, and Deborah L. Johnson*

Department of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine and Norris Comprehensive Cancer Center, 2011 Zonal Avenue, Los Angeles, California 90033

Received 20 February 2008/ Returned for modification 15 April 2008/ Accepted 6 August 2008

The epidermal growth factor receptor (EGFR) family regulates essential biological processes. Various epithelial tumors are linked to EGFR overexpression or expression of variant forms, such as the EGFR1 variant, EGFRvIII. Perturbations in expression of the transcription initiation factor, TATA-binding protein (TBP), alter cellular growth properties. Here we demonstrate that EGFR1 and EGFRvIII, but not HER2, induce TBP expression at a transcriptional level through distinct mechanisms. EGFR1 enhances the phosphorylation and function of Elk-1, recruiting it to the TBP promoter. In contrast, EGFRvIII robustly induces c-jun expression, stimulating recruitment of c-fos/c-jun to an overlapping AP-1 site. Enhancing c-jun expression alone induces TBP promoter activity through the AP-1 site. To determine the underlying mechanism for differences in Elk-1 function and c-jun expression by these receptors, we inhibited the internalization of EGFR1. Persistent EGFR1 cell surface occupancy mimics EGFRvIII-mediated effects on Elk-1 and c-jun and switches the requirement of Elk-1 to AP-1 for TBP promoter induction. Together, these studies define a new molecular mechanism for the regulation of TBP expression. In addition, we identify distinct molecular targets of EGFR1 and EGFRvIII and demonstrate the importance of receptor internalization in distinguishing their specific functions.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, University of Southern California, 2011 Zonal Avenue, HMR-600, Los Angeles, CA 90033. Phone: (323) 442-1446. Fax: (323) 442-1224. E-mail: johnsond{at}usc.edu

{triangledown} Published ahead of print on 18 August 2008.

Molecular and Cellular Biology, October 2008, p. 6483-6495, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00288-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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