Mdm4 loss in the intestinal epithelium leads to compartmentalized cell death but no tissue abnormalities.
Mdm4 is a critical inhibitor of the p53 tumor suppressor. Mdm4 null mice die early during embryogenesis due to increased p53 activity. In this study, we explore the role that Mdm4 plays in the intestinal epithelium by crossing mice carrying the Mdm4 floxed allele to mice with the Villin Cre transgene. Our data show that loss of Mdm4 (Mdm4intDelta) in this tissue resulted in viable animals with no obvious morphological abnormalities. However, these mutants displayed increased p53 levels and apoptosis exclusively in the proliferative compartment of the intestinal epithelium. This phenotype was completely rescued in a p53 null background. Notably, the observed compartmentalized apoptosis in proliferative intestinal epithelial cells was not due to restricted Mdm4 expression in this region. Thus, in this specific cellular context, p53 is negatively regulated by Mdm4 exclusively in highly proliferative cells.
Department of Genetics, Program in Genes and Development and Graduate School of Biomedical Sciences, University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Yasmine A
YA
Valentin-Vega
Neil
N
Box
Tamara
T
Terzian
Guillermina
G
Lozano
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001973:Bromodeoxyuridine / Q000378:metabolism; D003433:Crosses, Genetic; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D001616:beta-Galactosidase / Q000032:analysis / Q000378:metabolism
C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D001616:beta-Galactosidase; D001973:Bromodeoxyuridine