title: Multiple molecular interactions redundantly contribute to RB-mediated cell cycle control.
abstract: BACKGROUND
  The G1-S phase transition is critical to maintaining proliferative control and preventing carcinogenesis. The retinoblastoma tumor suppressor is a key regulator of this step in the cell cycle.
  
  
  RESULTS
  Here we use a structure-function approach to evaluate the contributions of multiple protein interaction surfaces on pRB towards cell cycle regulation. SAOS2 cell cycle arrest assays showed that disruption of three separate binding surfaces were necessary to inhibit pRB-mediated cell cycle control. Surprisingly, mutation of some interaction surfaces had no effect on their own. Rather, they only contributed to cell cycle arrest in the absence of other pRB dependent arrest functions. Specifically, our data shows that pRB-E2F interactions are competitive with pRB-CDH1 interactions, implying that interchangeable growth arrest functions underlie pRB's ability to block proliferation. Additionally, disruption of similar cell cycle control mechanisms in genetically modified mutant mice results in ectopic DNA synthesis in the liver.
  
  
  CONCLUSIONS
  Our work demonstrates that pRB utilizes a network of mechanisms to prevent cell cycle entry. This has important implications for the use of new CDK4/6 inhibitors that aim to activate this proliferative control network.
authors.affiliation: London Regional Cancer Program, London, Canada.|Department of Biochemistry, Western University, London, ON Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thwaites
authors.affiliation: London Regional Cancer Program, London, Canada.|Department of Biochemistry, Western University, London, ON Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Cecchini
authors.affiliation: London Regional Cancer Program, London, Canada.|Department of Biochemistry, Western University, London, ON Canada.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Talluri
authors.affiliation: London Regional Cancer Program, London, Canada.|Department of Biochemistry, Western University, London, ON Canada.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Passos
authors.affiliation: London Regional Cancer Program, London, Canada.|Department of Biochemistry, Western University, London, ON Canada.
authors.forename: Jasmyne
authors.initials: J
authors.lastname: Carnevale
authors.affiliation: London Regional Cancer Program, London, Canada.|Children's Health Research Institute, London, Canada.|Department of Biochemistry, Western University, London, ON Canada.
authors.forename: Frederick A
authors.identifier: 0000-0002-0047-9985
authors.initials: FA
authors.lastname: Dick
keywords: Cell cycle; Retinoblastoma; Structure–function; Systems biology; Tumor suppressor