| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 275, Issue 51, 40282-40287, December 22, 2000
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the 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
Inhibition of the Transforming Growth Factor
1 Signaling
Pathway by the AML1/ETO Leukemia-associated Fusion Protein*
§,,§,,
, and§**
Laboratory of Molecular Aspects of
Hematopoiesis, § Division of Hematologic Oncology, and
¶ Department of Medicine and the Cell Biology Program, Memorial
Sloan-Kettering Cancer Center, New York, New York 10021
1 (TGF-1) 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-1. 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-1 in stimulating reporter gene activity, whereas AML1/ETO represses basal promoter activity and blocks the response to TGF-1. Considering the
critical role of TGF-1 in the growth and differentiation of
hematopoietic cells, interference with TGF-1 signaling by AML1/ETO
may contribute to leukemogenesis.
*
This work was supported by United States Public Health
Service Grant DK43025 (to S. D. N.), The Lymphoma Foundation (to
A. J.), and Cancer Chemotherapy Training Program (to A. J.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Howard Hughes Medical Institute Investigator.
**
To whom correspondence should be addressed: Memorial
Sloan-Kettering Cancer Center, Box 575, 1275 York Ave., New York, NY 10021. Tel.: 212-639-7871; Fax: 212-794-5849; E-mail: s-nimer@mskcc.org.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  P. Su, F. Shafiee-Kermani, A. J. Gore, J. Jia, J. C. Wu, and W. L. Miller Expression and Regulation of the {beta}-Subunit of Ovine Follicle-Stimulating Hormone Relies Heavily on a Promoter Sequence Likely to Bind Smad-Associated Proteins Endocrinology, September 1, 2007; 148(9): 4500 - 4508. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Dong and G. C. Blobe Role of transforming growth factor-beta in hematologic malignancies Blood, June 15, 2006; 107(12): 4589 - 4596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kang, W. He, S. Tulley, G. P. Gupta, I. Serganova, C.-R. Chen, K. Manova-Todorova, R. Blasberg, W. L. Gerald, and J. Massague Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway PNAS, September 27, 2005; 102(39): 13909 - 13914. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. F.J.D. Benus, A. T.J. Wierenga, D. J.J. de Gorter, J. J. Schuringa, A. M. van Bennekum, L. Drenth-Diephuis, E. Vellenga, and B. J.L. Eggen Inhibition of the Transforming Growth Factor {beta} (TGF{beta}) Pathway by Interleukin-1{beta} Is Mediated through TGF{beta}-activated Kinase 1 Phosphorylation of SMAD3 Mol. Biol. Cell, August 1, 2005; 16(8): 3501 - 3510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-Y. Wang, G.-B. Zhou, T. Yin, B. Chen, J.-Y. Shi, W.-X. Liang, X.-L. Jin, J.-H. You, G. Yang, Z.-X. Shen, et al. AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: Implication in stepwise leukemogenesis and response to Gleevec PNAS, January 25, 2005; 102(4): 1104 - 1109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Scandura, P. Boccuni, J. Massague, and S. D. Nimer Transforming growth factor {beta}-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation PNAS, October 19, 2004; 101(42): 15231 - 15236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Chong, B. Ozdamar, J. L. Wrana, and J. D. Forman-Kay Disorder in a Target for the Smad2 Mad Homology 2 Domain and Its Implications for Binding and Specificity J. Biol. Chem., September 24, 2004; 279(39): 40707 - 40714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rabinovitch The Mouse Through the Looking Glass: A New Door Into the Pathophysiology of Pulmonary Hypertension Circ. Res., April 30, 2004; 94(8): 1001 - 1004. [Full Text] [PDF]
|
|
|
|
|
|
O. Heidenreich, J. Krauter, H. Riehle, P. Hadwiger, M. John, G. Heil, H.-P. Vornlocher, and A. Nordheim AML1/MTG8 oncogene suppression by small interfering RNAs supports myeloid differentiation of t(8;21)-positive leukemic cells Blood, April 15, 2003; 101(8): 3157 - 3163. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Liu, Y. Sun, F. Jiang, S. Zhang, Y. Wu, Y. Lan, X. Yang, and N. Mao Disruption of Smad5 gene leads to enhanced proliferation of high-proliferative potential precursors during embryonic hematopoiesis Blood, January 1, 2003; 101(1): 124 - 133. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
