Mdm2 is required for survival of hematopoietic stem cells/progenitors via dampening of ROS-induced p53 activity.
Mdm2 is an E3 ubiquitin ligase that targets p53 for degradation. p53(515C) (encoding p53R172P) is a hypomorphic allele of p53 that rescues the embryonic lethality of Mdm2(-/-) mice. Mdm2(-/-) p53(515C/515C) mice, however, die by postnatal day 13 resulting from hematopoietic failure. Hematopoietic stem cells and progenitors of Mdm2(-/-) p53(515C/515C) mice were normal in fetal livers but were depleted in postnatal bone marrows. After birth, these mice had elevated reactive oxygen species (ROS) thus activating p53R172P. In the absence of Mdm2, stable p53R172P induced ROS and cell cycle arrest, senescence, and cell death in the hematopoietic compartment. This phenotype was partially rescued with antioxidant treatment and upon culturing of hematopoietic cells in methycellulose at 3% oxygen. p16 was also stabilized because of ROS, and its loss increased cell cycling and partially rescued hematopoiesis and survival. Thus, Mdm2 is required to control ROS-induced p53 levels for sustainable hematopoiesis.
Program in Genes and Development of The Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Hussein A
HA
Abbas
Daniela R
DR
Maccio
Suleyman
S
Coskun
James G
JG
Jackson
Amy L
AL
Hazen
Tiffany M
TM
Sills
M James
MJ
You
Karen K
KK
Hirschi
Guillermina
G
Lozano
D000818:Animals; D002470:Cell Survival / Q000235:genetics; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2