Journal
GENES & DEVELOPMENT
Volume 22, Issue 8, Pages 992-997Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1651408
Keywords
hematopoietic stem cells; c-Cbl; thrombopoietin; STAT5; self-renewal
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NIDDK NIH HHS [DK072442] Funding Source: Medline
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Hematopoietic stem cells (HSCs) are multipotent progenitors that give rise to all types of blood cells. In the present study, we document that HSC development and functions are negatively regulated by the E3 ubiquitin ligase c-Cbl (casitas B-cell lymphoma). HSCs of c-Cbl(-/-) mice exhibit augmented pool size, hyperproliferation, greater competence, and enhanced long-term repopulating capacity. Our mechanistic studies identified that c-Cbl(-/-) HSCs are hyperresponsive to thrombopoietin (TPO) and display elevated levels of STAT5 phosphorylation, thus leading to increased c-Myc expression. In essence, our data unequivocally identify c-Cbl as a novel negative regulator of developmental and functional properties of HSCs.
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