Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7.
Ubiquitination is a posttranslational mechanism that controls diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes, including Notch1, c-Myc, and cyclin E. We have generated conditional Fbw7 knockout animals and inactivated the gene in hematopoietic stem cells (HSCs), progenitors, and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects hematopoiesis in a cell-autonomous manner. Fbw7(-/-) HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7(-/-) progenitors are unable to colonize the thymus, leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow (BM) stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E is visibly stabilized in the BM of Fbw7-deficient mice. Gene expression studies of Fbw7(-/-) HSCs and hematopoietic progenitors indicate that Fbw7 regulates, through the regulation of HSC cycle entry, the transcriptional "signature" that is associated with the quiescent, self-renewing HSC phenotype.
Thompson
Benjamin J
BJ
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Jankovic
Vladimir
V
Gao
Jie
J
Buonamici
Silvia
S
Vest
Alan
A
Lee
Jennifer May
JM
Zavadil
Jiri
J
Nimer
Stephen D
SD
Aifantis
Iannis
I
D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology; D016026:Bone Marrow Transplantation; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D047108:Embryonic Development; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D011995:Recombination, Genetic; D013601:T-Lymphocytes / Q000201:enzymology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D007527:Isoenzymes; D012333:RNA, Messenger; D011994:Recombinant Proteins; D044767:Ubiquitin-Protein Ligases