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Interchangeable Roles for E2F Transcriptional Repression by the Retinoblastoma Protein and p27KIP1--Cyclin-Dependent Kinase Regulation in Cell Cycle Control and Tumor Suppression.

Authors :
Thwaites, Michael J.
Cecchini, Matthew J.
Passos, Daniel T.
Welch, Ian
Dick, Frederick A.
Source :
Molecular & Cellular Biology. Jan2017, Vol. 37 Issue 2, p1-13. 13p.
Publication Year :
2017

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 (Rb1G) into a p27KIP1 null background (Cdkn1b-/-), both E2F transcriptional repression and CDK regulation are compromised. These double-mutant Rb1G/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 p27KIP1 leads to defective proliferative control in response to various types of DNA damage. In addition, Rb1G/G; Cdkn1b-/- fibroblasts immortalize faster in culture and more frequently than either single mutant genotype. Importantly, the synthetic DNA damage arrest defect caused by Rb1G/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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
02707306
Volume :
37
Issue :
2
Database :
Academic Search Index
Journal :
Molecular & Cellular Biology
Publication Type :
Academic Journal
Accession number :
120675206
Full Text :
https://doi.org/10.1128/MCB.00561-16