Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7 Journal Article
| Authors: | Thompson, B. J.; Jankovic, V.; Gao, J.; Buonamici, S.; Vest, A.; Lee, J. M.; Zavadil, J.; Nimer, S. D.; Aifantis, I. |
| Article Title: | Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7 |
| Abstract: | 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. © 2008 Thompson et al. The Rockefeller University Press. |
| Keywords: | controlled study; gene deletion; nonhuman; t-lymphocytes; animal cell; phenotype; animals; cell cycle proteins; mice; gene expression; animal experiment; transcription factor; cell renewal; cell differentiation; mice, inbred c57bl; b-lymphocytes; mice, transgenic; stem cell; gene expression regulation, developmental; tumor suppressor gene; regulatory mechanism; ubiquitination; rna, messenger; recombination, genetic; myc protein; recombinant proteins; hematopoietic stem cells; hematopoiesis; gene inactivation; hematopoietic stem cell; bone marrow transplantation; ubiquitin protein ligase e3; tumor suppressor protein; ubiquitin-protein ligases; embryonic development; cyclin e; isoenzymes; notch1 receptor; f-box proteins; gene expression regulation, enzymologic; fbw7 protein |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 205 |
| Issue: | 6 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2008-06-09 |
| Start Page: | 1395 |
| End Page: | 1408 |
| Language: | English |
| DOI: | 10.1084/jem.20080277 |
| PUBMED: | 18474632 |
| PROVIDER: | scopus |
| PMCID: | PMC2413036 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 28" - "Export Date: 17 November 2011" - "CODEN: JEMEA" - "Source: Scopus" |
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