GATA-3 regulates the self-renewal of long-term hematopoietic stem cells

被引：84

作者：

Frelin, Catherine ^{[1
,2
]}

Herrington, Robert ^{[1
]}

Janmohamed, Salima ^{[3
]}

Barbara, Mary ^{[1
]}

Tran, Gary ^{[1
,2
]}

Paige, Christopher J. ^{[1
,2
,3
]}

Benveniste, Patricia ^{[3
,4
]}

Zuniga-Pfluecker, Juan-Carlos ^{[3
,4
]}

Souabni, Abdallah ^{[5
]}

Busslinger, Meinrad ^{[5
]}

Iscove, Norman N. ^{[1
,2
,3
,6
]}

机构：

[1] Univ Hlth Network, Ontario Canc Inst, Toronto, ON, Canada

[2] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[3] Univ Toronto, Dept Immunol, Toronto, ON, Canada

[4] Sunnybrook Res Inst, Toronto, ON, Canada

[5] Res Inst Mol Pathol, A-1030 Vienna, Austria

[6] McEwen Ctr Regenerat Med, Toronto, ON, Canada

来源：

NATURE IMMUNOLOGY | 2013年 / 14卷 / 10期

基金：

加拿大健康研究院;

关键词：

P38; MAPK; PYRIMIDINYLIMIDAZOLE INHIBITORS; GENE-EXPRESSION; IN-VIVO; KINASE; CYTOKINE; DIFFERENTIATION; ALPHA; 5-FLUOROURACIL; AMPLIFICATION;

D O I：

10.1038/ni.2692

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

The transcription factor GATA-3 is expressed and required for differentiation and function throughout the T lymphocyte lineage. Despite evidence it may also be expressed in multipotent hematopoietic stem cells (HSCs), any role for GATA-3 in these cells has remained unclear. Here we found GATA-3 was in the cytoplasm in quiescent long-term stem cells from steady-state bone marrow but relocated to the nucleus when HSCs cycled. Relocation depended on signaling via the mitogen-activated protein kinase p38 and was associated with a diminished capacity for long-term reconstitution after transfer into irradiated mice. Deletion of Gata3 enhanced the repopulating capacity and augmented the self-renewal of long-term HSCs in cell-autonomous fashion without affecting the cell cycle. Our observations position GATA-3 as a regulator of the balance between self-renewal and differentiation in HSCs that acts downstream of the p38 signaling pathway.

引用

页码：1037 / +

页数：10

共 49 条

[1] Pyrimidinylimidazole inhibitors of p38: Cyclic N-1 imidazole substituents enhance p38 kinase inhibition and oral activity [J].

Adams, JL ;

Boehm, JC ;

Gallagher, TF ;

Kassis, S ;

Webb, EF ;

Hall, R ;

Sorenson, M ;

Garigipati, R ;

Griswold, DE ;

Lee, JC .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (21) :2867-2870

[2] Pyrimidinylimidazole inhibitors of CSBP/P37 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes [J].

Adams, JL ;

Boehm, JC ;

Kassis, S ;

Gorycki, PD ;

Webb, EF ;

Hall, R ;

Sorenson, M ;

Lee, JC ;

Ayrton, A ;

Griswold, DE ;

Gallagher, TF .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1998, 8 (22) :3111-3116

[3]

Barone FC, 2001, J PHARMACOL EXP THER, V296, P312

[4] Hematopoietic stem cells engraft in mice with absolute efficiency [J].

Benveniste, P ;

Cantin, C ;

Hyam, D ;

Iscove, NN .

NATURE IMMUNOLOGY, 2003, 4 (07) :708-713

[5] Intermediate-Term Hematopoietic Stem Cells with Extended but Time-Limited Reconstitution Potential [J].

Benveniste, Patricia ;

Frelin, Catherine ;

Janmohamed, Salima ;

Barbara, Mary ;

Herrington, Robert ;

Hyam, Deborah ;

Iscove, Norman N. .

CELL STEM CELL, 2010, 6 (01) :48-58

[6] Resolution of pluripotential intermediates in murine hematopoietic differentiation by global complementary DNA amplification from single cells: confirmation of assignments by expression profiling of cytokine receptor transcripts [J].

Billia, F ;

Barbara, M ;

McEwen, J ;

Trevisan, M ;

Iscove, NN .

BLOOD, 2001, 97 (08) :2257-2268

[7] Phenoxypyrimidine inhibitors of p38α kinase:: Synthesis and statistical evaluation of the p38 inhibitory potencies of a series of 1-(piperidin-4-yl)-4-(4-fluorophenyl)-5-2-phenoxypyrimidin-4-yl) imidazoles [J].

Boehm, JC ;

Bower, MJ ;

Gallagher, TF ;

Kassis, S ;

Johnson, SR ;

Adams, JL .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (09) :1123-1126

[8] Synergism of Toll-like receptor-induced interleukin-12p70 secretion by monocyte-derived dendritic cells is mediated through p38 MAPK and lowers the threshold of T-helper cell type I responses [J].

Bohnenkamp, Hermann R. ;

Papazisis, Konstantinos T. ;

Burchell, Joy M. ;

Taylor-Papadimitriou, Joyce .

CELLULAR IMMUNOLOGY, 2007, 247 (02) :72-84

[9] ANALYSIS OF GENE-EXPRESSION IN A COMPLEX DIFFERENTIATION HIERARCHY BY GLOBAL AMPLIFICATION OF CDNA FROM SINGLE CELLS [J].

BRADY, G ;

BILLIA, F ;

KNOX, J ;

HOANG, T ;

KIRSCH, IR ;

VOURA, EB ;

HAWLEY, RG ;

CUMMING, R ;

BUCHWALD, M ;

SIMINOVITCH, K ;

MIYAMOTO, N ;

BOEHMELT, G ;

ISCOVE, NN .

CURRENT BIOLOGY, 1995, 5 (08) :909-922

[10] GATA3 is redundant for maintenance and self-renewal of hematopoietic stem cells [J].

Buza-Vidas, Natalija ;

Duarte, Sara ;

Luc, Sidinh ;

Bouriez-Jones, Tiphaine ;

Woll, Petter S. ;

Jacobsen, Sten Eirik Waelgaard .

BLOOD, 2011, 118 (05) :1291-1293

← 1 2 3 4 5 →