Overproduction of MDM2 in vivo disrupts S phase independent of E2F1.

Abstract	Expression of a beta-lactoglobulin (BLG)/mdm2 transgene (BLGmdm2) in the epithelial cells of the mouse mammary gland causes an uncoupling of S phase from M phase, resulting in polyploidy and tumor formation. The cell cycle defects are independent of interactions with p53. Because MDM2 also binds and activates the S phase-specific transcription factor E2F1, we hypothesized that increased E2F1 activity causes the development of the BLGmdm2 phenotype. We, therefore, generated BLGmdm2 mice that were null for E2F1. We observed no notable differences in histology or cyclin gene expression between BLGmdm2 and BLGmdm2/E2F1-/- mice, indicating that endogenous E2F1 activity was not required for the BLGmdm2 phenotype. Because, depending on the experimental system, either loss of E2F1 function or overexpression of E2F1 results in transformation, we also tested whether overexpression of E2F1 augmented the severity of the BLGmdm2 phenotype by generating mice that were bitransgenic for BLGmdm2 and BLGE2F1. We observed a unique mixture of the two single transgenic phenotypes histologically and found no significant changes in cyclin levels, indicating that overexpression of E2F1 had no effect on the BLGmdm2 transgenic phenotype. Thus, increased expression or absence of E2F1 does not affect the ability of MDM2 to disrupt the cell cycle.
Authors	V Reinke, D M Bortner, L L Amelse, K Lundgren, M P Rosenberg, C A Finlay, G Lozano
Journal	Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research (Cell Growth Differ) Vol. 10 Issue 3 Pg. 147-54 (Mar 1999) ISSN: 1044-9523 [Print] United States
PMID	10099828 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References	Arid4a protein, mouse Carrier Proteins Cell Cycle Proteins Cyclin A Cyclin E DNA-Binding Proteins E2F Transcription Factors E2F1 Transcription Factor E2f1 protein, mouse Histones Nuclear Proteins Proto-Oncogene Proteins Retinoblastoma-Binding Protein 1 Transcription Factor DP1 Transcription Factors Tumor Suppressor Protein p53 Mdm2 protein, mouse Proto-Oncogene Proteins c-mdm2 Bromodeoxyuridine
Topics	Animals Breast (anatomy & histology) Bromodeoxyuridine (metabolism) Carrier Proteins Cell Cycle Proteins Cyclin A (metabolism) Cyclin E (metabolism) DNA-Binding Proteins E2F Transcription Factors E2F1 Transcription Factor Epithelial Cells Female Genotype Histones (metabolism) Mice Mice, Inbred C57BL Mice, Transgenic Models, Biological Nuclear Proteins Phenotype Proto-Oncogene Proteins (physiology) Proto-Oncogene Proteins c-mdm2 Retinoblastoma-Binding Protein 1 S Phase (physiology) Time Factors Transcription Factor DP1 Transcription Factors (physiology) Tumor Suppressor Protein p53 (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!