The E3 ubiquitin ligase c-Cbl restricts development and functions of hematopoietic stem cells

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...

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Bibliographic Details
Published in:Genes & development 2008-04, Vol.22 (8), p.992-997
Main Authors: Rathinam, Chozhavendan, Thien, Christine B F, Langdon, Wallace Y, Gu, Hua, Flavell, Richard A
Format: Article
Language:English
Subjects:
Animals
Cell Proliferation
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - enzymology
Mice
Mice, Transgenic
Phosphorylation
Proto-Oncogene Proteins c-cbl - genetics
Proto-Oncogene Proteins c-cbl - metabolism
Research Communication
STAT5 Transcription Factor - metabolism
Thrombopoietin - pharmacology
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.1651408