The Arf‐inducing transcription factor Dmp1 encodes a transcriptional activator of amphiregulin, thrombospondin‐1, JunB and Egr1

Abstract

Dmp1 (Dmtf1) encodes a Myb‐like transcription factor implicated in tumor suppression through direct activation of the Arf‐p53 pathway. The human DMP1 gene is frequently deleted in non‐small cell lung cancers, especially those that retain wild‐type INK4a/ARF and/or p53. To identify novel genes that are regulated by Dmp1, transcriptional profiles of lung tissue from Dmp1‐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 Dmp1. Notably, amphiregulin (Areg), thrombospondin‐1 (Tsp‐1), JunB, Egr1, adrenomedullin (Adm), Bcl‐3 and methyl‐CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1‐null mice while Gas1 and Ect2 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 Areg, Tsp‐1, JunB and Egr1. 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 de novo mRNA synthesis. Interestingly, these genes and their protein products were significantly downregulated or upregulated in the lungs from Dmp1‐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 Dmp1 in tumor suppression.

Regulation of murine hematopoietic stem cell quiescence by Dmtf1

“…41,42 A recent study implicated JunB as one of the targets of Dmtf1, showing that its expression was decreased in lung cells from Dmtf1-KO mice. 43 We therefore predicted reduced JunB expression in sorted KSL cells, B cells, and CD4 T cells from KO mice relative to similar WT cells ( Figure 6) and increased B-cell populations with reciprocal T-cell reductions in both primary KO mice and mice transplanted with KO BM cells (Table 1 and supplemental Figure 2). These findings are consistent with previous observations about distinctive JunB function in T and B cells, suggesting that JunB is potentially involved in a Dmtf1-mediated, Arf-independent pathway.…”

Aberrant expression of ETS1 and ETS2 proteins in cancer

“…Data from ChiP (99), Chip on Chip (169), and Chip-Seq (170) revealed that ~50% of promoters occupied by mtp53 contained ETS-binding sites, suggesting that physical binding with ETS proteins is an essential mechanism by which mtp53 regulates gene expression for oncogenic transformation (159, 160). Importantly, these mtp53-bound genomic regions do not have a WTp53 response element 5′-PuPuPuC(A/T)(A/T)GPyPyPy-3 (171), indicating that the mtp53 proteins do not cause transformation through direct binding to DNA (159).…”

Regulation of transcription factors via natural decoys in genomic DNA

“…In fact, for example, a study using Dmp1 C/C , Dmp1 C/¡ , and Dmp1 ¡/¡ mice showed such results for the transcription factor Dmp1 (Dmtf1). 21 The on-off switchlike response via NDs may also be relevant to a sharp spatial boundary of expression in response to the gradient of the transcription factor Bicoid, a morphogen in Drosophila development. 7 In the switch model, as long as a transition between the "on" and "off" phases is involved, even a relatively moderate up or downregulation of a transcription factor may result in drastic changes in expression levels of its target genes.…”