TY - JOUR
T1 - RB Restricts DNA Damage-Initiated Tumorigenesis through an LXCXE-Dependent Mechanism of Transcriptional Control
AU - Bourgo, Ryan J.
AU - Thangavel, Chellappagounder
AU - Ertel, Adam
AU - Bergseid, Jacqueline
AU - Kathleen McClendon, A.
AU - Wilkens, Ludwig
AU - Witkiewicz, Agnieszka K.
AU - Wang, Jean Y J
AU - Knudsen, Erik S.
N1 - Funding Information:
The authors thank Gustavo Leone for generously providing mouse embryonic fibroblasts for study of E2F3 function. Karen Knudsen, Matthew Schiever, and Elizabeth Schade graciously contributed to the editing of the manuscript. E.S.K. is supported by grant CA127387. J.Y.J.W. is supported by grant CA058320.
PY - 2011/8/19
Y1 - 2011/8/19
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2011.06.029
DO - 10.1016/j.molcel.2011.06.029
M3 - Article
C2 - 21855804
AN - SCOPUS:80051748549
SN - 1097-2765
VL - 43
SP - 663
EP - 672
JO - Molecular cell
JF - Molecular cell
IS - 4
ER -