QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 15, Issue 7, 3450-3463, July 2004

This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: E03-11-0807v1 15/7/3450    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schulze, A. Articles by Downward, J. Search for Related Content PubMed PubMed Citation Articles by Schulze, A. Articles by Downward, J.

The Transcriptional Response to Raf Activation Is Almost Completely Dependent on Mitogen-activated Protein Kinase Kinase Activity and Shows a Major Autocrine Component

Almut Schulze ^* , Barbara Nicke , Patricia H. Warne , Simon Tomlinson , and Julian Downward 

^* Gene Expression Analysis, Cancer Research UK London Research Institute, London WC2A 3PX, United Kingdom; Signal Transduction, Cancer Research UK London Research Institute, London WC2A 3PX, United Kingdom; and Comparative Genome Analysis Laboratories, Cancer Research UK London Research Institute, London WC2A 3PX, United Kingdom

Submitted November 13, 2003; Revised March 8, 2004; Accepted March 29, 2004
Monitoring Editor: Anne Ridley

The Raf protein kinases are major effectors of Ras GTPases and key components of the transcriptional response to serum factors, acting at least in part through the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. It has recently been suggested that Raf also may trigger other as yet uncharacterized signaling pathways. Here, we have used cDNA microarrays to dissect changes in gene expression induced by activation of inducible c-Raf-1 constructs in human mammary epithelial and ovarian epithelial cells. The majority of Raf-induced transcriptional responses are shown to be blocked by pharmacological inhibition of the Raf substrate mitogen-activated protein kinase kinase, indicating that potential mitogen-activated protein kinase kinase-independent Raf signaling pathways have no significant influence on gene expression. In addition, we used epidermal growth factor receptor inhibitory drugs to address the contribution of autocrine signaling by Raf-induced EGF family proteins to the Raf transcriptional response. At least one-half of the transcription induced by Raf activation requires epidermal growth factor (EGF) receptor function The EGF receptor-independent component of the Raf transcriptional response is entirely up-regulation of gene expression, whereas the EGF receptor-dependent component is an equal mixture of up- and down-regulation. The use of transcriptional profiling in this way allows detailed analysis of the architecture of signaling pathways to be undertaken.

Online version of this article contains supporting material. Online version is available at www.molbiolcell.org.

Corresponding author. E-mail address: almut.schulze{at}cancer.org.uk.

This article has been cited by other articles:

				J. J.-C. Sheu, C.-H. Hua, L. Wan, Y.-J. Lin, M.-T. Lai, H.-C. Tseng, N. Jinawath, M.-H. Tsai, N.-W. Chang, C.-F. Lin, et al. Functional Genomic Analysis Identified Epidermal Growth Factor Receptor Activation as the Most Common Genetic Event in Oral Squamous Cell Carcinoma Cancer Res., March 15, 2009; 69(6): 2568 - 2576. [Abstract] [Full Text] [PDF]

				M. S. Anglesio, J. M. Arnold, J. George, A. V. Tinker, R. Tothill, N. Waddell, L. Simms, B. Locandro, S. Fereday, N. Traficante, et al. Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors Mol. Cancer Res., November 1, 2008; 6(11): 1678 - 1690. [Abstract] [Full Text] [PDF]

				G. Rocher, C. Letourneux, P. Lenormand, and F. Porteu Inhibition of B56-containing Protein Phosphatase 2As by the Early Response Gene IEX-1 Leads to Control of Akt Activity J. Biol. Chem., February 23, 2007; 282(8): 5468 - 5477. [Abstract] [Full Text] [PDF]

				J. M. Shields, N. E. Thomas, M. Cregger, A. J. Berger, M. Leslie, C. Torrice, H. Hao, S. Penland, J. Arbiser, G. Scott, et al. Lack of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Signaling Shows a New Type of Melanoma Cancer Res., February 15, 2007; 67(4): 1502 - 1512. [Abstract] [Full Text] [PDF]

				K. Ehrenreiter, D. Piazzolla, V. Velamoor, I. Sobczak, J. V. Small, J. Takeda, T. Leung, and M. Baccarini Raf-1 regulates Rho signaling and cell migration J. Cell Biol., March 14, 2005; 168(6): 955 - 964. [Abstract] [Full Text] [PDF]