Regulation of the MAD1 promoter by G-CSF.
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/EBPalpha and beta 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/EBPbeta. In summary, our studies provide a first analysis of the MAD1 promoter and suggest STAT3 functions as a C/EBPbeta 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.
Jiang
Kan
K
Institut für Biochemie, Universitätsklinikum, RWTH Aachen University, Pauwelsstrasse 30, 52057 Aachen, Germany.
Hein
Nadine
N
Eckert
Kolja
K
Lüscher-Firzlaff
Juliane
J
Lüscher
Bernhard
B
D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry; D017930:Genes, Reporter; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D051381:Rats; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D020218:Response Elements; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction; D015533:Transcriptional Activation
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D022762:CCAAT-Enhancer-Binding Proteins; D002843:Chromatin; C079439:MXD1 protein, human; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D016179:Granulocyte Colony-Stimulating Factor