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TISSUE-SPECIFIC STEM CELLS

TIS21^/BTG2 Negatively Regulates Estradiol-Stimulated Expansion of Hematopoietic Stem Cells by Derepressing Akt Phosphorylation and Inhibiting mTOR Signal Transduction

^aDepartment of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, Korea;
^bDepartment of Physiology and Functional Genomics, University of Florida, Gainesville, Florida, USA

Key Words. TIS21^/BTG2/PC3 • Estrogen • Hematopoietic stem cells • Protein kinase B • Extracellular signal-regulated kinase 1/2 • Mammalian target of rapamycin

Correspondence: Correspondence: In Kyoung Lim, M.D., Ph.D., Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, 443-721, Korea. Telephone: +82-31-219-5051; Fax: +82-31-219-5059; e-mail: iklim{at}ajou.ac.kr

Received on April 1, 2008; accepted for publication on May 27, 2008.

First published online in STEM CELLS EXPRESS  June 12, 2008.

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 17β-estradiol (E₂)-regulated progenitor expansion. E₂ induced DNA synthesis and cell proliferation of mouse embryonic fibroblasts (MEFs) isolated from TIS21^–/– mice, but not wild type (WT). In contrast to WT, E₂ 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. E₂-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 E₂-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.

Disclosure of potential conflicts of interest is found at the end of this article.

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