Regulation of hematopoietic stem cell differentiation by a single ubiquitin ligase-substrate complex

被引：92

作者：

Reavie, Linsey ^{[1
,2
,3
]}

Della Gatta, Giusy ^{[4
]}

Crusio, Kelly ^{[1
,2
,3
]}

Aranda-Orgilles, Beatriz ^{[1
,2
,3
]}

Buckley, Shannon M. ^{[1
,2
,3
]}

Thompson, Benjamin ^{[1
,2
,3
]}

Lee, Eugine ^{[1
,2
,3
]}

Gao, Jie ^{[1
,2
,3
]}

Bredemeyer, Andrea L. ^{[5
]}

Helmink, Beth A. ^{[5
]}

Zavadil, Jiri ^{[3
,6
]}

Sleckman, Barry P. ^{[5
]}

Palomero, Teresa ^{[4
]}

Ferrando, Adolfo ^{[4
]}

Aifantis, Iannis ^{[1
,2
,3
]}

机构：

[1] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10012 USA

[2] NYU, Sch Med, Dept Pathol, New York, NY USA

[3] NYU, Sch Med, Inst Canc, New York, NY USA

[4] Columbia Univ, Inst Canc Genet, New York, NY USA

[5] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA

[6] NYU, Sch Med, Ctr Hlth Informat & Bioinformat, New York, NY USA

来源：

NATURE IMMUNOLOGY | 2010年 / 11卷 / 03期

基金：

美国国家卫生研究院;

关键词：

C-MYC; SELF-RENEWAL; TUMOR-SUPPRESSOR; EXPRESSION; QUIESCENCE; MICROARRAY; INSIGHTS; BIOLOGY; CYCLE; ACTS;

D O I：

10.1038/ni.1839

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Hematopoietic stem cell (HSC) differentiation is regulated by cell-intrinsic and cell-extrinsic cues. In addition to transcriptional regulation, post-translational regulation may also control HSC differentiation. To test this hypothesis, we visualized the ubiquitin-regulated protein stability of a single transcription factor, c-Myc. The stability of c-Myc protein was indicative of HSC quiescence, and c-Myc protein abundance was controlled by the ubiquitin ligase Fbw7. Fine changes in the stability of c-Myc protein regulated the HSC gene-expression signature. Using whole-genome genomic approaches, we identified specific regulators of HSC function directly controlled by c-Myc binding; however, adult HSCs and embryonic stem cells sensed and interpreted c-Myc-regulated gene expression in distinct ways. Our studies show that a ubiquitin ligase-substrate pair can orchestrate the molecular program of HSC differentiation.

引用

页码：207 / U3

页数：11

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