Expression of constitutively active Notch4 (Int-3) modulates myeloid proliferation and differentiation and promotes expansion of hematopoietic progenitors Journal Article
| Authors: | Ye, Q.; Shieh, J.H.; Morrone, G.; Moore, M. A. S. |
| Article Title: | Expression of constitutively active Notch4 (Int-3) modulates myeloid proliferation and differentiation and promotes expansion of hematopoietic progenitors |
| Abstract: | The Notch family of transmembrane receptors has been implicated in the regulation of many developmental processes. In this study, we evaluated the role of Notch4 in immature hematopoietic progenitors by inducing, with retroviral transduction, enforced expression of Int-3, the oncogenic and constitutively active form of mouse Notch4. Int-3-transduced human myeloid leukemia (HL-60) cells demonstrated significantly delayed expression of differentiation markers following retinoic acid and 12-0-tetradecanoylphorbol 13-acetate treatment. Furthermore, HL-60 cells expressing Int-3 displayed a slower growth rate than cells infected with void virus, and accumulation in the G0/G1 phases of cell cycle. Transduction with deletion mutants of Int-3 defined the importance of individual domains of the protein (in particular, the ANK domain and the C-terminal domain) in the inhibition of differentiation and growth arrest of HL-60 cells. When mouse bone marrow enriched for stem cells (5-fluorouracil-resistant, lineage negative) was transduced and cultured for two weeks, the Int-3-transduced population displayed a lower expression of differentiation markers and a three- to five-fold higher frequency of colony-forming cells (CFU-GM/BFU-E) than control cultures. These results strongly support the notion that Notch signaling inhibits differentiation and promotes expansion of hematopoietic stem/progenitor cells. © 2004 Nature Publishing Group. All rights reserved. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; human cell; proto-oncogene proteins; fluorouracil; mutant protein; protein domain; cell proliferation; animals; mice; cell division; cell growth; carboxy terminal sequence; cell line; notch receptor; cell differentiation; transfection; mice, inbred balb c; stem cell; cell culture; leukemia cell; receptors, notch; hematopoietic stem cells; hematopoiesis; protein structure, tertiary; bone marrow cell; hematopoietic stem cell; protein folding; protein family; retinoic acid; cell cycle g1 phase; cell cycle g0 phase; retrovirus; differentiation; phorbol esters; growth rate; receptors, cell surface; notch4 receptor; phorbol 13 acetate 12 myristate; colony forming cell; myeloid cells; myeloid leukemia; tretinoin; myelopoiesis; membrane receptor; hl-60 cells; humans; human; priority journal; article; int-3; notch4 |
| Journal Title: | Leukemia |
| Volume: | 18 |
| Issue: | 4 |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2004-04-01 |
| Start Page: | 777 |
| End Page: | 787 |
| Language: | English |
| DOI: | 10.1038/sj.leu.2403291 |
| PROVIDER: | scopus |
| PUBMED: | 14961038 |
| DOI/URL: | |
| Notes: | Leukemia -- Cited By (since 1996):19 -- Export Date: 16 June 2014 -- CODEN: LEUKE -- Source: Scopus |
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