Interchangeable Roles for E2F Transcriptional Repression by the Retinoblastoma Protein and p27^KIP1–Cyclin-Dependent Kinase Regulation in Cell Cycle Control and Tumor Suppression

ABSTRACT

The mammalian G₁-S phase transition is controlled by the opposing forces of cyclin-dependent kinases (CDK) and the retinoblastoma protein (pRB). Here, we present evidence for systems-level control of cell cycle arrest by pRB-E2F and p27-CDK regulation. By introducing a point mutant allele of pRB that is defective for E2F repression (Rb1^G) into a p27^KIP1 null background (Cdkn1b^−/−), both E2F transcriptional repression and CDK regulation are compromised. These double-mutant Rb1^G/G; Cdkn1b^−/− mice are viable and phenocopy Rb1^+/− mice in developing pituitary adenocarcinomas, even though neither single mutant strain is cancer prone. Combined loss of pRB-E2F transcriptional regulation and p27^KIP1 leads to defective proliferative control in response to various types of DNA damage. In addition, Rb1^G/G; Cdkn1b^−/− fibroblasts immortalize faster in culture and more frequently than either single mutant genotype. Importantly, the synthetic DNA damage arrest defect caused by Rb1^G/G; Cdkn1b^−/− mutations is evident in the developing intermediate pituitary lobe where tumors ultimately arise. Our work identifies a unique relationship between pRB-E2F and p27-CDK control and offers in vivo evidence that pRB is capable of cell cycle control through E2F-independent effects.

KEYWORDS:

• cell cycle
• DNA damage
• tumor suppressor
• CDK
• E2F
• DNA damage checkpoints
• cyclin-dependent kinases
• tumor suppressor genes

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Articles of Significant Interest Selected from This Issue by the Editors

ACKNOWLEDGMENTS

We thank Ashley Watson and Nathalie Bérubé for their technical expertise for pituitary sectioning and staining, as well as Charles Ishak, Gabe DiMattia, and Joe Mymryk for frequent discussions and experimental advice.

M.J.T. was funded by OGS, and M.J.T. and M.J.C. were members of the CIHR Strategic Training Program in Cancer Research (CaRTT). M.J.C. was a recipient of a CIHR MD/Ph.D. studentship. F.A.D. is the Wolfe Senior Fellow in Tumor Suppressor Genes. This work was funded by an operating grant from the CIHR (MOP-89765) to F.A.D.