Document Detail


Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression.
MedLine Citation:
PMID:  22958933     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Pten deletion from adult mouse hematopoietic cells activates the PI3-kinase pathway, inducing hematopoietic stem cell (HSC) proliferation, HSC depletion, and leukemogenesis. Pten is also mutated in human leukemias, but rarely in early childhood leukemias. We hypothesized that this reflects developmental changes in PI3-kinase pathway regulation. Here we show that Rictor deletion prevents leukemogenesis and HSC depletion after Pten deletion in adult mice, implicating mTORC2 activation in these processes. However, Rictor deletion had little effect on the function of normal HSCs. Moreover, Pten deletion from neonatal HSCs did not activate the PI3-kinase pathway or promote HSC proliferation, HSC depletion, or leukemogenesis. Pten is therefore required in adult, but not neonatal, HSCs to negatively regulate mTORC2 signaling. This demonstrates that some critical tumor suppressor mechanisms in adult cells are not required by neonatal cells. Developmental changes in key signaling pathways therefore confer temporal changes upon stem cell self-renewal and tumor suppressor mechanisms.
Authors:
Jeffrey A Magee; Tsuneo Ikenoue; Daisuke Nakada; Jae Y Lee; Kun-Liang Guan; Sean J Morrison
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cell stem cell     Volume:  11     ISSN:  1875-9777     ISO Abbreviation:  Cell Stem Cell     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-10     Completed Date:  2013-05-29     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101311472     Medline TA:  Cell Stem Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  415-28     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Affiliation:
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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MeSH Terms
Descriptor/Qualifier:
Aging / pathology
Animals
Animals, Newborn
Carrier Proteins / metabolism
Cell Proliferation
Enzyme Activation
Gene Deletion
Hematopoietic Stem Cell Mobilization
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells / enzymology*,  pathology*
Humans
Leukemia / enzymology,  pathology*,  prevention & control*
Mice
Mice, Inbred C57BL
Multiprotein Complexes / metabolism*
PTEN Phosphohydrolase / metabolism*
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction
TOR Serine-Threonine Kinases / metabolism*
Time Factors
Tumor Suppressor Protein p53 / metabolism
Grant Support
ID/Acronym/Agency:
R01 CA108941/CA/NCI NIH HHS; R37 AG024945/AG/NIA NIH HHS; R37 AG024945/AG/NIA NIH HHS; //Howard Hughes Medical Institute; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Carrier Proteins; 0/Multiprotein Complexes; 0/TOR complex 2; 0/Tumor Suppressor Protein p53; 0/rictor protein, mouse; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.1.3.48/Pten protein, mouse; EC 3.1.3.67/PTEN Phosphohydrolase
Comments/Corrections
Comment In:
Cell Stem Cell. 2012 Sep 7;11(3):281-2   [PMID:  22958924 ]

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