The hDMP1 tumor suppressor is a new WT1 target in myeloid leukemias

Tschan, Mario P.; Gullberg, Urban; Shan, Deborah; Torbett, BE; Fey, MF; Tobler, Andreas

doi:10.1038/sj.leu.2405018

Cited by 11 publications

(13 citation statements)

References 7 publications

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“…Since Egr1 is a direct transcriptional target of Dmp1, it is very likely that Dmp1 deletion leads to lung cancer development by lowering Egr1 levels. Of note, Tschan et al recently showed that the WT1, which has significant structural homology with Egr1, repressed the h DMP1 promoter through direct binding to the Egr1/Sp1 site 12. Thus, it is possible that Egr1, like JunB, is located both upstream and downstream of the Dmp1 signaling, both contributing to tumor suppression.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, the Dmp1 promoter is repressed by physiological mitogenic stimuli and overexpression of E2F proteins 9. The Dmp1 promoter is also repressed by genotoxic stimuli mediated by NF-κB11 and by the Wilms tumor gene product, WT1 12. Both Dmp1 -knockout and heterozygous mice are prone to tumor development.…”

Section: Introductionmentioning

confidence: 99%

“…9 The Dmp1 promoter is also repressed by genotoxic stimuli mediated by NF-jB 11 and by the Wilms tumor gene product, WT1. 12 Both Dmp1-knockout and heterozygous mice are prone to tumor development. Tumors isolated from Dmp1 þ/À mice seldom lose the wild-type Dmp1 allele, indicating that Dmp1 is haplo-insufficient for tumor suppression.…”

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confidence: 99%

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

Mallakin

Sugiyama

Kai

et al. 2009

Intl Journal of Cancer

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Mallakin

Sugiyama

Kai

et al. 2009

Intl Journal of Cancer

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“… 47 – 49 The human DMP1 gene ( hDMP1 ) expression is suppressed by WT1 in leukemic cells via direct binding to an EGR/SP1 site, delineating a new oncogenic WT1 mechanism of control in the hematopoietic system. 50 Eµ - Myc -, K-ras LA -, and HER2/neu -driven tumor development was significantly accelerated in both Dmp1 +/− and Dmp1 −/− mice, with no significant differences in the survival between the two cohorts, suggesting that Dmp1 is a haploinsufficient tumor suppressor. 45 , 51 – 53 In Eµ - Myc lymphomas, the combined frequencies of p53 mutation and Arf deletion in mice of Dmp1 +/− or Dmp1 −/− background were significantly lower than that in Dmp1 +/+ littermates, indicating that Dmp1 is a physiological regulator of the Arf-p53 pathway in vivo.…”

Section: Introductionmentioning

confidence: 91%

Novel Molecular Markers for Breast Cancer

Inoue

Fry

2016

Biomark�Cancer

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The use of molecular biomarkers assures that breast cancer (BC) patients receive optimal treatment. Established biomarkers, such as estrogen receptor, progesterone receptor, HER2, and Ki67, have been playing significant roles in the subcategorization of BC to predict the prognosis and decide the specific therapy to each patient. Antihormonal therapy using 4-hydroxytamoxifen or aromatase inhibitors have been employed in patients whose tumor cells express hormone receptors, while monoclonal antibody to HER2 has been administered to HER2-positive BCs. Although new therapeutic agents have been developed in the past few decades, many patients still die of the disease due to relapse; thus, novel molecular markers that predict therapeutic failure and those that can be targets for specific therapy are expected. We have chosen four of such molecules by reviewing recent publications, which are cyclin E, B-Myb, Twist, and DMP1β. The oncogenicity of these molecules has been demonstrated in vivo and/or in vitro through studies using transgenic mice or siRNAs, and their expressions have been shown to be associated with shortened overall or disease-free survival of BC patients. The former three molecules have been shown to accelerate epithelial–mesenchymal transition that is often associated with cancer stem cell-ness and metastasis; all these four can be novel therapeutic targets as well. Thus, large prospective studies employing immunohistochemistry will be needed to establish the predictive values of these molecules in patients with BC.

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“…(ATP-binding cassette, sub-family B (MDR/TAP), member 1; MDR1) 32 and anti-apoptotic BCL2A1 (BCL2-related protein A1; BFL1), 33 while being a transcriptional suppressor of tumour suppressors, among them the cell cycle inhibitor DMTF1 (cyclin D binding Myb-like transcription factor 1; hDMP1) 34 and an anti-proliferative differentiation inducer, IRF8 (interferon regulatory factor 8). 35 Thus, a growing body of evidence indicates WT1 as an oncogene in AML.…”

Section: Wt1 As An Oncogene In Cancer and Acute Myeloid Leukaemiamentioning

confidence: 99%