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 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.
Rathinam
Chozhavendan
C
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Thien
Christine B F
CB
Langdon
Wallace Y
WY
Gu
Hua
H
Flavell
Richard A
RA
D000818:Animals; D049109:Cell Proliferation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013926:Thrombopoietin / Q000494:pharmacology
D050799:STAT5 Transcription Factor; D013926:Thrombopoietin; D050721:Proto-Oncogene Proteins c-cbl