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A retinoblastoma allele that is mutated at its common E2F interaction site inhibits cell proliferation in gene-targeted mice
Molecular and Cellular Biology
  • Matthew J. Cecchini, Western University
  • Michael J. Thwaites, Western University
  • Srikanth Talluri, Western University
  • James I. MacDonald, Western University
  • Daniel T. Passos, Western University
  • Jean Leon Chong, The Ohio State University
  • Paul Cantalupo, University of Pittsburgh
  • Paul M. Stafford, Western University
  • M. Teresa Sáenz-Robles, University of Pittsburgh
  • Sarah M. Francis, Western University
  • James M. Pipas, University of Pittsburgh
  • Gustavo Leone, The Ohio State University
  • Ian Welch, Western University
  • Frederick A. Dick, Western University
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The retinoblastoma protein (pRB) is best known for regulating cell proliferation through E2F transcription factors. In this report, we investigate the properties of a targeted mutation that disrupts pRB interactions with the transactivation domain of E2Fs. Mice that carry this mutation endogenously (Rb1δG) are defective for pRB-dependent repression of E2F target genes. Except for an accelerated entry into S phase in response to serum stimulation, cell cycle regulation in Rb1δG/δG mouse embryonic fibroblasts (MEFs) strongly resembles that of the wild type. In a serum deprivation-induced cell cycle exit, Rb1δG/δG MEFs display a magnitude of E2F target gene derepression similar to that of Rb1-/- cells, even though Rb1δG/δG cells exit the cell cycle normally. Interestingly, cell cycle arrest in Rb1δG/δG MEFs is responsive to p16 expression and gamma irradiation, indicating that alternate mechanisms can be activated in G1 to arrest proliferation. Some Rb1δG/δG mice die neonatally with a muscle degeneration phenotype, while the others live a normal life span with no evidence of spontaneous tumor formation. Most tissues appear histologically normal while being accompanied by derepression of pRB-regulated E2F targets. This suggests that non- E2F-, pRB-dependent pathways may have a more relevant role in proliferative control than previously identified. © 2014, American Society for Microbiology.

Citation Information
Matthew J. Cecchini, Michael J. Thwaites, Srikanth Talluri, James I. MacDonald, et al.. "A retinoblastoma allele that is mutated at its common E2F interaction site inhibits cell proliferation in gene-targeted mice" Molecular and Cellular Biology Vol. 34 Iss. 11 (2014) p. 2029 - 2045
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