Distinct roles of Mdm2 and Mdm4 in red cell production.
Mdm2 and Mdm4 are critical negative regulators of the p53 tumor suppressor. Mdm4-null mutants are severely anemic and exhibit impaired proliferation of the fetal liver erythroid lineage cells. This phenotype may indicate a cell-intrinsic function of Mdm4 in erythropoiesis. In contrast, red blood cell count was nearly normal in mice engineered to express low levels of Mdm2, suggesting that Mdm2 might be dispensable for red cell production. Here, we further explore the tissue-specific functions of Mdm2 and Mdm4 in the erythroid lineage by intercrossing conditional Mdm4 and Mdm2 alleles to an erythroid-specific Cre (Er-GFP-Cre) knock-in allele. Our data show that Mdm2 is required for rescuing erythroid progenitors from p53-mediated apoptosis during primitive erythropoiesis. In contrast, Mdm4 is only required for the high erythropoietic rate during embryonic definitive erythropoiesis. Thus, in this particular cellular context, Mdm4 only contributes to p53 regulation at a specific phase of the differentiation program.
Maetens
Marion
M
Laboratory for Molecular Cancer Biology, Flanders Institute for Biotechnology (VIB), University of Ghent, Belgium.
Doumont
Gilles
G
Clercq
Sarah De
SD
Francoz
Sarah
S
Froment
Pascal
P
Bellefroid
Eric
E
Klingmuller
Ursula
U
Lozano
Guillermina
G
Marine
Jean-Christophe
JC
D000375:Aging; D000818:Animals; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology* / Q000378:metabolism*; D004920:Erythropoiesis; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases