title: RB deletion disrupts coordination between DNA replication licensing and mitotic entry in vivo.
abstract: The integrity of the retinoblastoma tumor suppressor (RB) pathway is critical for restraining inappropriate proliferation and suppressing tumor development in a plethora of tissues. Here adenovirus-mediated RB deletion in the liver of adult mice led to DNA replication in the absence of productive mitotic condensation. The replication induced by RB loss was E2F-mediated and associated with the induction of DNA damage and a nontranscriptional G2/M checkpoint that targeted the accumulation of Cyclin B1. In the context of RB deletion or E2F activation, there was an increase in hepatocyte ploidy that was accompanied by hyperphysiological assembly of prereplication complexes. In keeping with this dysregulation, initiation of DNA replication was readily observed in hepatocytes that were phenotypically in G2/M. Under such conditions, uncoupling of replication initiation from mitotic progression led to altered genome ploidy in the liver. Interestingly, these findings in hepatocytes were not recapitulated in the basally proliferative tissues of the gastrointestinal tract, where RB deletion, while increasing DNA replication, did not lead to a profound uncoupling from mitosis. Combined, these findings demonstrate the critical role of RB in controlling cell-cycle transitions and underscore the importance of intrinsic tissue environments in resultant phenotypes.
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: Ursula
authors.initials: U
authors.lastname: Ehmer
authors.forename: Julien
authors.initials: J
authors.lastname: Sage
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D056744:Cyclin B1 / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication; D050684:E2F Transcription Factors / Q000378:metabolism; D017353:Gene Deletion; D008099:Liver / Q000473:pathology / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis / Q000502:physiology*; D011003:Ploidies; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D056744:Cyclin B1; D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein