Regulation of hematopoietic stem cell differentiation by a single ubiquitin ligase–substrate complex
Open Access
- 17 January 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Immunology
- Vol. 11 (3), 207-215
- https://doi.org/10.1038/ni.1839
Abstract
Hematopoietic stem cells infrequently proliferate, but their self-renewal is essential. Aifantis and colleagues show regulation of c-Myc protein stability by the ubiquitin ligase Fbw7 controls the self-renewal and differentiation potential of these cells. 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.Keywords
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