1. RB restricts DNA damage-initiated tumorigenesis through an LXCXE-dependent mechanism of transcriptional control.
- Author
-
Bourgo RJ, Thangavel C, Ertel A, Bergseid J, McClendon AK, Wilkens L, Witkiewicz AK, Wang JY, and Knudsen ES
- Subjects
- Amino Acid Motifs, Animals, Binding Sites, Cell Line, Chromatin metabolism, Humans, Mice, Protein Interaction Domains and Motifs, Protein Interaction Mapping, Retinoblastoma Protein chemistry, Retinoblastoma Protein metabolism, DNA Damage, Gene Expression Regulation, Retinoblastoma Protein physiology, Transcription, Genetic
- Abstract
The LXCXE peptide motif facilitates interaction between the RB tumor suppressor and a large number of cellular proteins that are expected to impinge on diverse biological processes. In vitro and in vivo analyses demonstrated that LXCXE binding function is dispensable for RB promoter association and control of basal gene expression. Dependence on this function of RB is unmasked after DNA damage, wherein LXCXE binding is essential for exerting control over E2F3 and suppressing cell-cycle progression in the presence of genotoxic stress. Gene expression profiling revealed that the transcriptional program coordinated by this specific aspect of RB is associated with progression of human hepatocellular carcinoma and poor disease outcome. Consistent with these findings, biological challenge revealed a requirement for LXCXE binding in suppression of genotoxin-initiated hepatocellular carcinoma in vivo. Together, these studies establish an essential role of the LXCXE binding motif for RB-mediated transcriptional control, response to genotoxic insult, and tumor suppression., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF