Faculty Collaboration Database

A retinoblastoma allele that is mutated at its common E2F interaction site inhibits cell proliferation in gene-targeted mice. Mol Cell Biol 2014 Jun;34(11):2029-45

Date

03/26/2014

Pubmed ID

24662053

Pubmed Central ID

PMC4019062

DOI

10.1128/MCB.01589-13

Scopus ID

2-s2.0-84899888987 (requires institutional sign-in at Scopus site)   25 Citations

Abstract

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 (Rb1(ΔG)) 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 Rb1(ΔG/ΔG) mouse embryonic fibroblasts (MEFs) strongly resembles that of the wild type. In a serum deprivation-induced cell cycle exit, Rb1(ΔG/ΔG) MEFs display a magnitude of E2F target gene derepression similar to that of Rb1(-/-) cells, even though Rb1(ΔG/ΔG) cells exit the cell cycle normally. Interestingly, cell cycle arrest in Rb1(ΔG/ΔG) MEFs is responsive to p16 expression and gamma irradiation, indicating that alternate mechanisms can be activated in G1 to arrest proliferation. Some Rb1(ΔG/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.

Author List

Cecchini MJ, Thwaites MJ, Talluri S, MacDonald JI, Passos DT, Chong JL, Cantalupo P, Stafford PM, Sáenz-Robles MT, Francis SM, Pipas JM, Leone G, Welch I, Dick FA

Author

Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Alleles
Animals
Binding Sites
Cell Line
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p16
E2F Transcription Factors
Fibroblasts
Gene Targeting
Mice
Mice, Knockout
Mutation
Pituitary Neoplasms
Retinoblastoma Protein
S Phase
S Phase Cell Cycle Checkpoints