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.
| Original language | English |
|---|---|
| Pages (from-to) | 40282-40287 |
| Number of pages | 6 |
| Journal | Journal of Biological Chemistry |
| Volume | 275 |
| Issue number | 51 |
| DOIs | |
| State | Published - Dec 22 2000 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry
Cite this
Inhibition of the transforming growth factor β1 signaling pathway by the AML1/ETO leukemia-associated fusion protein. / Jakubowiak, Andrzej; Pouponnot, Celio; Berguido, Francisco; Frank, Richard; Mao, Shifeng; Massagué, Joan; Nimer, Stephen D.
In: Journal of Biological Chemistry, Vol. 275, No. 51, 22.12.2000, p. 40282-40287.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inhibition of the transforming growth factor β1 signaling pathway by the AML1/ETO leukemia-associated fusion protein
AU - Jakubowiak, Andrzej
AU - Pouponnot, Celio
AU - Berguido, Francisco
AU - Frank, Richard
AU - Mao, Shifeng
AU - Massagué, Joan
AU - Nimer, Stephen D
PY - 2000/12/22
Y1 - 2000/12/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0034704128&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034704128&partnerID=8YFLogxK
U2 - 10.1074/jbc.C000485200
DO - 10.1074/jbc.C000485200
M3 - Article
VL - 275
SP - 40282
EP - 40287
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 51
ER -