title: RB restricts DNA damage-initiated tumorigenesis through an LXCXE-dependent mechanism of transcriptional control.
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.
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Bourgo
authors.forename: Chellappagounder
authors.initials: C
authors.lastname: Thangavel
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bergseid
authors.forename: A Kathleen
authors.initials: AK
authors.lastname: McClendon
authors.forename: Ludwig
authors.initials: L
authors.lastname: Wilkens
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
authors.forename: Jean Y J
authors.initials: JY
authors.lastname: Wang
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D016160:Retinoblastoma Protein