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Title: Mdm2 is required for survival of hematopoietic stem cells/progenitors via dampening of ROS-induced p53 activity

Author
item ABBAS, HUSSEIN - Md Anderson Cancer Center
item MACCIO, DANIELA - Md Anderson Cancer Center
item COSKUN, SULEYMAN - Baylor College Of Medicine
item JACKSON, JAMES - Md Anderson Cancer Center
item HAZEN, AMY - Md Anderson Cancer Center
item SILLS, TIFFANY - Baylor College Of Medicine
item YOU, M - Md Anderson Cancer Center
item HIRSCHI, KAREN - Children'S Nutrition Research Center (CNRC)
item LOZANO, GUILLERMINA - Md Anderson Cancer Center

Submitted to: Cell Stem Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/25/2010
Publication Date: 11/4/2010
Citation: Abbas, H.A., Maccio, D.R., Coskun, S., Jackson, J.G., Hazen, A.L., Sills, T.M., You, M.J., Hirschi, K.K., Lozano, G. 2010. Mdm2 is required for survival of hematopoietic stem cells/progenitors via dampening of ROS-induced p53 activity. Cell Stem Cell. 7(5):606-617.

Interpretive Summary: There is a specific enzyme (Mdm2, or murine double minute oncogene) found in mice that degrades protein p53 (also known as tumor protein 53) which suppresses tumors and is involved in preventing cancer. If too much Mdm2 is produced in the body, cancer tumor formation is increased; however, if Mdm2 is completely absent, the animal cannot live and dies while the fetus is developing in the uterus. If another protein very similar to p53 is made available, this will prevent death before the fetus is born, but the pup will still die within 2 weeks after birth due to problems with the generation of blood-related stem cells. Blood-related stem cells (called Hematopoietic Stem Cells, or HSCs, from now on), are very premature precursor cells in their very early development which will become blood or blood-related cells as they mature). This research has shown that the HSCs are normal in the fetal mice that have the protein similar to p53, but they are depleted within 2 weeks after birth. Through these experiments, it was discovered that these mice had an elevated reactive oxygen species (also known as ROS, which are highly reactive molecules that contain oxygen). Therefore after the pups that were missing Mdm2 were born, the elevated reactive oxygen species caused normally dividing HSCs to stop their division, become prematurely old, and die. Thus, Mdm2 is required to control ROS-induced p53 levels for long-term generation of blood cells (and all blood-related cells).

Technical Abstract: 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.