Expression of Dmp1 in specific differentiated, nonproliferating cells and its regulation by E2Fs

Mallakin, Ali; Taneja, Pankaj; Matise, Lauren A.; Inoue, Kazushi

doi:10.1038/sj.onc.1209750

Cited by 33 publications

(75 citation statements)

References 40 publications

(52 reference statements)

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“…Although the Dmp1 promoter is activated by oncogenic Ras signaling, it was repressed when the cells entered the S to G2/M phase of the cell cycle when both Dmp1 and Arf expressions were downregulated (Mallakin et al, 2006). Subsets of E2Fs were specifically bound to the Dmp1 promoter upon mitogenic signaling, and E2Fs 1-4 inhibited the Dmp1 promoter in a reporter assay.…”

Section: Regulation Of Dmp1 By E2fs and Its Expression In Specific DImentioning

confidence: 96%

“…It is important to note that the Dmp1 promoter is not the only promoter repressed by 'activating' E2Fs; repression of the human telomerase promoter as well as the tumor suppressor ARHI promoter by E2F1 have also been reported (Crowe et al, 2001;Lu et al, 2006). Although the detailed mechanism of E2F-mediated repression of the Dmp1 promoter remains to be determined, one preliminary experiment suggests that the repression is Rb-independent since the E2F1 Y411C mutant that does not interact with Rb (Rowland et al, 2002) inhibited the Dmp1 promoter as well (Mallakin et al, 2006).…”

Section: Dmp1 Review K Inoue Et Almentioning

confidence: 99%

“…Surprisingly, all of the E2F1, E2F2 and E2F3a proteins were repressors on the Dmp1 promoter, especially the former two. Thus, E2F1 has differential effects on the Dmp1 promoter (repression) and the Arf promoter (activation) when overexpressed in rodent fibroblasts (Inoue et al, 1999;Mallakin et al, 2006). The E2F-mediated regulation of the Dmp1 promoter is conserved in humans since the hDMP1 promoter has a typical E2F site (5 0 -TTTCGCGC) and is efficiently repressed by E2Fs (Inoue K et al, unpublished data).…”

Section: Dmp1 Review K Inoue Et Almentioning

confidence: 99%

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Dmp1 and tumor suppression

2007

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Section: Regulation Of Dmp1 By E2fs and Its Expression In Specific DImentioning

confidence: 96%

Section: Dmp1 Review K Inoue Et Almentioning

confidence: 99%

Section: Dmp1 Review K Inoue Et Almentioning

confidence: 99%

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Dmp1 and tumor suppression

2007

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“…For analysis of Dmp1, p19 Arf , p53, p21 Cip1 and actin, affinitypurified polyclonal antibodies to the mouse Dmp1 (RAX, Mallakin et al, 2006), p19 Arf (sc-32748, Santa Cruz Biotechnology, Santa Cruz, CA, USA), p53 (sc-6243G), p21 Cip1 (sc-6246) or Actin (sc-1615), were used, followed by incubation of the filters with HRP-conjugated second antibodies, reaction with the enhanced ECL detection kit (PerkinElmer, Boston, MA, USA).…”

Section: Western Blottingmentioning

confidence: 99%

“…On the other hand, the Dmp1 promoter is repressed by overexpression of E2Fs and physiological mitogenic signaling. Thus, Dmp1 is a novel marker of cells that have exited from the cell cycle (Mallakin et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Repression of Dmp1 and Arf transcription by anthracyclins: critical roles of the NF-κB subunit p65

et al. 2007

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Both genotoxic and oncogenic stress activates the nuclear factor-kappa B (NF-jB) and p53 proteins; however, the p53 activity is antagonized by NF-jB signaling. Dmp1 is a Myb-like transcription factor that activates the Arf-p53 pathway. The Dmp1 promoter was activated by a classical NF-jB activator tumor necrosis factor a, but repressed by treatment of cells with non-classical NF-jB activators, anthracyclins and UV-C. p65 and other subsets of NF-jB proteins were bound to the Dmp1 promoter following anthracyclin/UV-C treatment of rodent fibroblasts. This resulted in the downregulation of Dmp1 mRNA and protein. Repression of the Dmp1 transcription by anthracyclins depended on the unique NF-jB site on the promoter. Downregulation of p65 significantly attenuated the repression of the Dmp1 promoter by anthracyclins/ UV-C. The amount of Dmp1 bound to the Arf promoter decreased significantly upon anthracyclin treatment; this, in turn, downregulated the Arf levels. Repression of the Arf promoter by p65 or anthracyclins depended on Dmp1, which was significantly attenuated in Dmp1 À/À cells. Both Dmp1 À/À and Arf À/À cells showed resistance to anthracyclininduced cell death compared to wild-type cells; non-immortalized p65-knockdown cells were much more sensitive. Thus, the Dmp1-Arf pathway is repressed by p65 in response to genotoxic stress, which implicates a novel mechanism of p53 inactivation by NF-jB.

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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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Expression of Dmp1 in specific differentiated, nonproliferating cells and its regulation by E2Fs

Cited by 33 publications

References 40 publications

Dmp1 and tumor suppression

Dmp1 and tumor suppression

Repression of Dmp1 and Arf transcription by anthracyclins: critical roles of the NF-κB subunit p65

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

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