Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Mol. Cell. Biol. 28 (20): 6483-6495

Copyright © 2008 by the 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 for publication 20 February 2008. Revision received 15 April 2008. Accepted for publication 6 August 2008.

Abstract: 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.



THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Covalent Small Ubiquitin-like Modifier (SUMO) Modification of Maf1 Protein Controls RNA Polymerase III-dependent Transcription Repression.
A. D. Rohira, C.-Y. Chen, J. R. Allen, and D. L. Johnson (2013)
J. Biol. Chem. 288, 19288-19295
   Abstract »    Full Text »    PDF »
Ctip2 is a dynamic regulator of epidermal proliferation and differentiation by integrating EGFR and Notch signaling.
L.-j. Zhang, S. Bhattacharya, M. Leid, G. Ganguli-Indra, and A. K. Indra (2012)
J. Cell Sci. 125, 5733-5744
   Abstract »    Full Text »    PDF »
Single-cell proteomic chip for profiling intracellular signaling pathways in single tumor cells.
Q. Shi, L. Qin, W. Wei, F. Geng, R. Fan, Y. Shik Shin, D. Guo, L. Hood, P. S. Mischel, and J. R. Heath (2012)
PNAS 109, 419-424
   Abstract »    Full Text »    PDF »
Alcohol Induces RNA Polymerase III-dependent Transcription through c-Jun by Co-regulating TATA-binding Protein (TBP) and Brf1 Expression.
S. Zhong, K. Machida, H. Tsukamoto, and D. L. Johnson (2011)
J. Biol. Chem. 286, 2393-2401
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882