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TIS21/(BTG2) negatively regulates estradiol-stimulated expansion of hematopoietic stem cells by derepressing Akt phosphorylation and inhibiting mTOR signal transduction.

Authors
Kim, BC; Ryu, MS; Oh, SP; Lim, IK
Citation
Stem cells, 26(9):2339-2348, 2008
Journal Title
Stem cells
ISSN
0250-6793
Abstract
It has been known that 12-O-tetradecanoyl phorbol-13-acetate-inducible sequence 21 (TIS21), ortholog of human B-cell translocation gene 2, regulates expansions of stage-specific thymocytes and hematopoietic progenitors. In the present study, lineage-negative (Lin(-))/stem cell antigen-1-positive (Sca-1+)/c-Kit+ (LSK) cell content was significantly elevated in bone marrow (BM) of TIS21-knockout (TIS21(-/-)) female mice, suggesting 17beta-estradiol (E(2))-regulated progenitor expansion. E(2) induced DNA synthesis and cell proliferation of mouse embryonic fibroblasts (MEFs) isolated from TIS21(-/-) mice, but not wild type (WT). In contrast to WT, E(2) failed to activate protein kinase B (Akt) in the TIS21(-/-) MEFs, independent of extracellular signal-regulated kinase 1/2 (Erk1/2) activation. Despite attenuation of Akt activation, mammalian target of rapamycin (mTOR) was constitutively activated in the TIS21(-/-) MEFs. Furthermore, mitogen-activated protein kinase 1/2 inhibitor or knockdown of Erk1 could restore activation of Akt and downregulate mTOR. Immunoprecipitation showed Akt preferentially bound to phosphorylated Erk1/2 (p-Erk1/2) in TIS21(-/-) cells, but reconstitution of TIS21 inhibited their interaction. E(2)-injected TIS21(-/-) male mice also increased LSK cells in BM. Taken together, expansion of hematopoietic progenitors in TIS21(-/-) female mice might be through inhibition of Akt activation, and constitutive activation of mTOR via preferential binding of TIS21 to E(2)-induced p-Erk1/2, compared with that of Akt. Our results suggest that TIS21 plays a pivotal role in maintaining the hematopoietic stem cell compartment and hematopoiesis.
MeSH terms
AnimalsCarrier Proteins/physiology*Cell Proliferation/drug effectsCells, CulturedEstradiol/pharmacology*Extracellular Signal-Regulated MAP Kinases/metabolismFemaleFibroblasts/cytologyFibroblasts/drug effectsFibroblasts/metabolismGenes, Tumor Suppressor/physiology*Hematopoietic Stem Cells/cytology*Hematopoietic Stem Cells/drug effectsHematopoietic Stem Cells/metabolismImmediate-Early Proteins/physiology*MaleMiceMice, KnockoutPhosphorylationPhosphotransferases (Alcohol Group Acceptor)/physiology*Proto-Oncogene Proteins c-akt/metabolismSignal TransductionTOR Serine-Threonine KinasesTumor Suppressor Proteins
DOI
10.1634/stemcells.2008-0327
PMID
18556508
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Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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