Nucleic Acids Research Advance Access originally published online on January 18, 2008
Nucleic Acids Research 2008 36(5):1517-1531; doi:10.1093/nar/gkn002
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Nucleic Acids Research, 2008, Vol. 36, No. 5 1517-1531
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Regulation of the MAD1 promoter by G-CSF
Institut für Biochemie, Universitätsklinikum, RWTH Aachen University, Pauwelsstrasse 30, 52057 Aachen, Germany
*To whom correspondence should be addressed. Tel: +49 241 8088850; Fax: +49 241 8082427; Email: luescher{at}rwth-aachen.de
Received September 7, 2007. Revised December 16, 2007. Accepted January 1, 2008.
MAD family proteins are transcriptional repressors that antagonize the functions of MYC oncoproteins. In particular, MAD1 has been demonstrated to interfere with MYC-induced proliferation, transformation and apoptosis. The MAD1 gene is expressed in distinct patterns, mainly associated with differentiation and quiescence. We observed that MAD1 is directly activated by G-CSF in promyelocytic cell lines. To investigate the transcriptional regulation of the human MAD1 gene, we have cloned and characterized its promoter. A region of high homology between the MAD1 orthologs of human, mouse and rat contains the core promoter, marked by open chromatin, high GC content and the lack of a TATA box. Using deletion constructs we identified two CCAAT-boxes occupied by C/EBP
and β in the homology region that mediate responsiveness to G-CSF receptor signaling. The necessary signals include the activation of STAT3 and the RAS/RAF/ERK pathway. STAT3 does not bind directly to promoter DNA, but is recruited by C/EBPβ. In summary, our studies provide a first analysis of the MAD1 promoter and suggest STAT3 functions as a C/EBPβ cofactor in the regulation of the MAD1 gene. Our findings provide the base for the characterization of additional signal transduction pathways that control the expression of MAD1.
Present addresses: Kan Jiang, Department of Haematology and the MRC Molecular Haematology Unit, John Radcliffe Hospital and the Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Kolja Eckert Abteilung für Kinderchirurgie, Elisabeth-Krankenhaus, 45138 Essen, Germany.
The authors wish it to be known that, in their opinion, the second and third authors should be regarded as joint Second Authors.