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Media type:
E-Article
Title:
The Arf‐inducing transcription factor Dmp1 encodes a transcriptional activator of amphiregulin, thrombospondin‐1, JunB and Egr1
Contributor:
Mallakin, Ali;
Sugiyama, Takayuki;
Kai, Fumitake;
Taneja, Pankaj;
Kendig, Robert D.;
Frazier, Donna P.;
Maglic, Dejan;
Matise, Lauren A.;
Willingham, Mark C.;
Inoue, Kazushi
imprint:
Wiley, 2010
Published in:International Journal of Cancer
Language:
English
DOI:
10.1002/ijc.24938
ISSN:
0020-7136;
1097-0215
Origination:
Footnote:
Description:
<jats:title>Abstract</jats:title><jats:p>Dmp1 (Dmtf1) encodes a Myb‐like transcription factor implicated in tumor suppression through direct activation of the Arf‐p53 pathway. The human <jats:italic>DMP1</jats:italic> gene is frequently deleted in non‐small cell lung cancers, especially those that retain wild‐type <jats:italic>INK4a/ARF</jats:italic> and/or <jats:italic>p53</jats:italic>. To identify novel genes that are regulated by Dmp1, transcriptional profiles of lung tissue from <jats:italic>Dmp1</jats:italic>‐null and wild‐type mice were generated using the GeneChip Microarray. Comparative analysis of gene expression changes between the two groups resulted in identification of numerous genes that may be regulated by <jats:italic>Dmp1</jats:italic>. Notably, amphiregulin (<jats:italic>Areg</jats:italic>), thrombospondin‐1 (<jats:italic>Tsp‐1</jats:italic>), <jats:italic>JunB</jats:italic>, <jats:italic>Egr1</jats:italic>, adrenomedullin (<jats:italic>Adm</jats:italic>), <jats:italic>Bcl‐3</jats:italic> and methyl‐CpG binding domain protein 1 (<jats:italic>Mbd1</jats:italic>) were downregulated in the lungs from <jats:italic>Dmp1</jats:italic>‐null mice while <jats:italic>Gas1</jats:italic> and <jats:italic>Ect2</jats:italic> genes were upregulated. These target genes were chosen for further analyses since they are involved in cell proliferation, transcription, angiogenesis/metastasis, apoptosis, or DNA methylation, and thus could account for the tumor suppressor phenotype of Dmp1. Dmp1 directly bound to the genomic loci of <jats:italic>Areg</jats:italic>, <jats:italic>Tsp‐1</jats:italic>, <jats:italic>JunB</jats:italic> and <jats:italic>Egr1</jats:italic>. Significant upregulation or downregulation of the novel Dmp1 target genes was observed upon transient expression of Dmp1 in alveolar epithelial cells, an effect which was nullified by the inhibition of <jats:italic>de novo</jats:italic> mRNA synthesis. Interestingly, these genes and their protein products were significantly downregulated or upregulated in the lungs from <jats:italic>Dmp1</jats:italic>‐heterozygous mice as well. Identification of novel Dmp1 target genes not only provides insights into the effects of Dmp1 on global gene expression, but also sheds light on the mechanism of haploid insufficiency of <jats:italic>Dmp1</jats:italic> in tumor suppression.</jats:p>