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Transcriptional Regulation of the TATA-Binding Protein by Ras Cellular Signaling

Johnson, Sandra A. S. and Mandavia, Nihar and Wang, Horng-Dar and Johnson, Deborah L. (2000) Transcriptional Regulation of the TATA-Binding Protein by Ras Cellular Signaling. Molecular and Cellular Biology, 20 (14). pp. 5000-5009. ISSN 0270-7306.

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Our previous studies have demonstrated that the level of the central transcription factor TATA-binding protein (TBP) is increased in cells expressing the hepatitis B virus (HBV) X protein through the activation of the Ras signaling pathway, which serves to enhance both RNA polymerase I and III promoter activities. To understand the mechanism by which TBP is regulated, we have investigated whether enhanced expression is modulated at the transcriptional level. Nuclear run-on assays revealed that the HBV X protein increases the number of active transcription complexes on the TBP gene. In transient-transfection assays with both transformed and primary hepatocytes, the human TBP promoter was shown to be induced by expression of the HBV X protein in a Ras-dependent manner, requiring both Ral guanine nucleotide dissociation stimulator (RalGDS) and Raf signaling. Transient overexpression of TBP did not affect TBP promoter activity. To further delineate the downstream Ras-mediated events contributing to TBP promoter regulation in primary rat hepatocytes, the best-characterized Ras effectors, Raf, phosphoinositide 3-kinase (PI-3 kinase), and RalGDS, were examined. Activation of either Raf or RalGDS, but not that of PI-3 kinase, was sufficient to induce TBP promoter activity. Both Raf- and RalGDS-mediated induction required the activation of mitogen-activated protein kinase kinase (MEK). In addition, another distinct Ras-activated pathway, which does not require MEK activation, appears to induce TBP promoter activity. Analysis of the DNA sequence requirement within the TBP promoter responsible for these regulatory events defined three distinct regions that modulate the abilities of Raf, RalGDS, and the Ras-dependent, MEK-independent pathways to regulate human TBP promoter activity. Together, these results provide new evidence that TBP can be regulated at the transcriptional level and identify three distinct Ras-activated pathways that modulate this central eukaryotic transcription factor.

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Additional Information:Copyright © 2000, American Society for Microbiology. Received 1 December 1999/Returned for modification 6 January 2000/Accepted 19 April 2000 We are grateful for many helpful discussions with the Gene Regulation Group at the USC Norris Comprehensive Cancer Center and Daniel Broek. We thank Michael White (University of Texas Southwest Medical Center) for many of the signaling protein expression vectors, as well as his guidance. Diane Hawley (University of Oregon) is acknowledged for her generous gift of the hTBP promoter and mutant constructs. We are grateful to George Ingersoll and Andrew Dervan for their superb technical assistance and the USC Liver Core Facility. This work was supported by National Institutes of Health grant CA74138 to D.L.J. and a grant from the Margaret E. Earley Research Trust. S.S.J. was supported in part by a postdoctoral fellowship from the USC Norris Comprehensive Cancer Center.
Issue or Number:14
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ID Code:1823
Deposited By: Archive Administrator
Deposited On:19 Feb 2006
Last Modified:02 Oct 2019 22:47

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