Inhibition of the transforming growth factor β1 signaling pathway by the AML1/ETO leukemia-associated fusion protein Journal Article
| Authors: | Jakubowiak, A.; Pouponnot, C.; Berguido, F.; Frank, R.; Mao, S.; Massagué, J.; Nimer, S. D. |
| Article Title: | Inhibition of the transforming growth factor β1 signaling pathway by the AML1/ETO leukemia-associated fusion protein |
| Abstract: | The t(8;21) translocation, found in adult acute myelogenous leukemia, results in the formation of an AML1/ETO chimeric transcription factor. AML1/ETO expression leads to alterations in hematopoietic progenitor cell differentiation, although its role in leukemic transformation is not clear. The N-terminal portion of AML1, which is retained in AML1/ETO, contains a region of homology to the FAST proteins, which cooperate with Smads to regulate transforming growth factor β1 (TGF-β1) target genes. We have demonstrated the physical association of Smad proteins with AML1 and AML1/ETO by immunoprecipitation and have mapped the region of interaction to the runt homology domain in these AML1 proteins. Using confocal microscopy, we demonstrated that AML1, and ETO and/or AML1/ETO, colocalize with Smads in the nucleus of t(8;21)-positive Kasumi-1 cells, in the presence but not the absence of TGF-β1. Using transient transfection assays and a reporter gene construct that contains both Smad and AML1 consensus binding sequences, we demonstrated that overexpression of AML1B cooperates with TGF-β1 in stimulating reporter gene activity, whereas AML1/ETO represses basal promoter activity and blocks the response to TGF-β1. Considering the critical role of TGF-β1 in the growth and differentiation of hematopoietic cells, interference with TGF-β1 signaling by AML1/ETO may contribute to leukemogenesis. |
| Keywords: | signal transduction; unclassified drug; acute granulocytic leukemia; promoter region; nonhuman; protein domain; protein localization; animal cell; animals; mice; gene overexpression; cell growth; transforming growth factor beta; protein protein interaction; cell protein; transcription factor; cell differentiation; cos cells; animalia; transcription factors; amino terminal sequence; genetic transfection; leukemogenesis; oncogene proteins, fusion; reporter gene; transforming growth factor beta1; base sequence; dna primers; malignant transformation; core binding factor alpha 2 subunit; 3t3 cells; priority journal; article; leukemia associated fusion protein |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 275 |
| Issue: | 51 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2000-12-22 |
| Start Page: | 40282 |
| End Page: | 40287 |
| Language: | English |
| DOI: | 10.1074/jbc.C000485200 |
| PUBMED: | 11032826 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 18 November 2015 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work