A retinoblastoma allele that is mutated at its common E2F interaction site inhibits cell proliferation in gene targeted mice

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 (Rb1DeltaG) are defective in regulating E2F target genes. Surprisingly, cell cycle regulation in Rb1DeltaG/DeltaG MEFs strongly resembles that of wild type. In a serum deprivation induced cell cycle exit, Rb1DeltaG/DeltaG MEFs display a similar magnitude of E2F target gene derepression as Rb1-/-, even though Rb1DeltaG/DeltaG cells exit the cell cycle normally. Interestingly, cell cycle arrest in Rb1DeltaG/DeltaG MEFs is responsive to p16 expression, indicating that the DeltaG-pRB protein can be activated in G1 to arrest proliferation through non-E2F mechanisms. Some Rb1DeltaG/DeltaG mice die neonatally with a muscle degeneration phenotype, while the others live a normal lifespan with no evidence of spontaneous tumor formation. Histological analysis reveals discrete examples of hyperplasia in the mammary epithelium, but most tissues appear 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. Total RNA was extracted from littermate paired WT, DeltaG and null MEFs induced to enter quiencense by Serum deprivation. Expresssion levels were analyzed by Affymetrix GeneChip Mouse Gene 1.0ST Array. Relative expression was determined by BRB-Array Tools software to generate RMA values.

ORGANISM(S): Mus musculus

SUBMITTER: Fred Dick 

PROVIDER: E-GEOD-54924 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress