| Note | The human DMTF1alpha protein consists of 760 amino acids; DMTF1beta, 272 amino acids; and DMTF1gamma, 285 amino acids. Mouse Dmp1 consists of 761 amino acids. |
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| | Proteins generated from splicing variants of the human DMTF1 gene. The hDMTF1 beta and gamma isoforms lack most of the Myb-like repeats and the principal transactivation domains, and thus, they do not bind to DNA. |
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| Description | Dmtf1 is a MYB-like transcription factor isolated in a yeast two-hybrid screen of a mouse T lymphocyte library with cyclin D2 bait. It binds to a consensus sequence CCCG(G/T)ATG(T/C) that is also recognized by Ets family proteins. DMTF1 is a novel tumor suppressor that receives signals from oncogenic RAS and activates the ARF - P53 pathway. D-type cyclins antagonize the activity of Dmtf1 when E2F sites are not on the promoter; however, they synergize with Dmtf1 on the Arf promoter. Recent study shows significant involvement of DMTF1 in human non-small-cell lung carcinomas. |
| Expression | Mouse Dmtf1 protein is expressed in the testis, thymus, spleen, brain, lung, and kidney. |
| Localisation | Both human and mouse DMTF1 alpha proteins are localized in the nucleus. |
| Function | Dmtf1-null mice are prone to spontaneous tumor development, which was accelerated when the animals were neonatally treated with ionizing radiation or dimethylbenzanthracene. Lung adenomas/adenocarcinomas were the most common tumors found in Dmtf1-deficient mice. Eµ-Myc-induced lymphomagenesis was significantly accelerated in Dmtf1-deficient mice. The retention and expression of the wild-type Dmtf1 allele in tumors arising in heterozygotes indicated that Dmtf1 is haplo-insufficient for tumor suppression. The low frequency of Arf deletion and p53 mutation in tumors from Dmtf1-knockout mice suggested that Dmtf1 is a physiological regulator of the Arf-p53 pathway in vivo.
The DMTF1 promoter is activated by the oncogenic RAS - RAF - MEK - ERK - JUN pathway, and the induction of ARF by RAS is DMTF1-dependent. Thus, DMTF1 is a critical mediator of p19ARF in response to oncogenic RAS signaling. The importance of dmp1 in P53 regulation was recently demonstrated by crossing Dmtf1-deficient mice with K-rasLA transgenic mice. The Dmtf1 promoter is repressed by overexpression of E2Fs and also by physiological mitogenic signaling. Thus, DMTF1 is a marker of cells that have exited from the cell cycle. The DMTF1 promoter is repressed by genotoxic stimuli mediated by NF-kappa B, and repression of the ARF promoter by genotoxic stimuli is DMP1-dependent. Very little studies have been conducted on the post-translational modifications for DMTF1. |
| Homology | Human DMTF1 vs. mouse Dmtf1: 95% (723/761), positives 97% (739/761) at the amino acids level.
Mouse Dmtf1 vs. mouse TTF-1 (transcription termination factor 1): Identities 29% (90/309), positives 47% (148/309).
Mouse Dmtf1 vs. mouse C-myb: Identities 32% (23/71), positives 54% (39/71).
Mouse Dmtf1 vs. mouse A-myb: Identities 29% (31/106), positives 50% (54/106).
Mouse Dmtf1 vs. mouse B-myb: Identities 27% (22/80), positives 53% (43/80) |
| Interaction of D-type cyclins with a novel myb-like transcription factor, DMP1. |
| Hirai H, Sherr CJ. |
| Mol Cell Biol. 1996 Nov;16(11):6457-67. |
| PMID 8887674 |
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| Gene expression and cell cycle arrest mediated by transcription factor DMP1 is antagonized by D-type cyclins through a cyclin-dependent-kinase-independent mechanism. |
| Inoue K, Sherr CJ. |
| Mol Cell Biol. 1998 Mar;18(3):1590-600. |
| PMID 9488476 |
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| Regulation of the CD13/aminopeptidase N gene by DMP1, a transcription factor antagonized by D-type cyclins. |
| Inoue K, Sherr CJ, Shapiro LH. |
| J Biol Chem. 1998 Oct 30;273(44):29188-94. |
| PMID 9786929 |
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| Cloning and chromosomal localization of the gene encoding human cyclin D-binding Myb-like protein (hDMP1). |
| Bodner SM, Naeve CW, Rakestraw KM, Jones BG, Valentine VA, Valentine MB, Luthardt FW, Willman CL, Raimondi SC, Downing JR, Roussel MF, Sherr CJ, Look AT. |
| Gene. 1999 Mar 18;229(1-2):223-8. |
| PMID 10095122 |
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| Induction of ARF tumor suppressor gene expression and cell cycle arrest by transcription factor DMP1. |
| Inoue K, Roussel MF, Sherr CJ. |
| Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3993-8. |
| PMID 10097151 |
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| Disruption of the ARF transcriptional activator DMP1 facilitates cell immortalization, Ras transformation, and tumorigenesis. |
| Inoue K, Wen R, Rehg JE, Adachi M, Cleveland JL, Roussel MF, Sherr CJ. |
| Genes Dev. 2000 Jul 15;14(14):1797-809. |
| PMID 10898794 |
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| Dmp1 is haplo-insufficient for tumor suppression and modifies the frequencies of Arf and p53 mutations in Myc-induced lymphomas. |
| Inoue K, Zindy F, Randle DH, Rehg JE, Sherr CJ. |
| Genes Dev. 2001 Nov 15;15(22):2934-9. |
| PMID 11711428 |
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| Alternative splicing of the human cyclin D-binding Myb-like protein (hDMP1) yields a truncated protein isoform that alters macrophage differentiation patterns. |
| Tschan MP, Fischer KM, Fung VS, Pirnia F, Borner MM, Fey MF, Tobler A, Torbett BE. |
| J Biol Chem. 2003 Oct 31;278(44):42750-60. |
| PMID 12917399 |
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| Ras-Raf-Arf signaling critically depends on the Dmp1 transcription factor. |
| Sreeramaneni R, Chaudhry A, McMahon M, Sherr CJ, Inoue K. |
| Mol Cell Biol. 2005 Jan;25(1):220-32. |
| PMID 15601844 |
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| Expression of Dmp1 in specific differentiated, nonproliferating cells and its regulation by E2Fs. |
| Mallakin A, Taneja P, Matise LA, Willingham MC, Inoue K. |
| Oncogene. 2006 Dec 14;25(59):7703-13. |
| PMID 16878159 |
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| Inoue K, Mallakin A, Frazier DP. |
| Oncogene. 2007 Jun 28;26(30):4329-35. |
| PMID 17237816 |
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| Mutually exclusive inactivation of DMP1 and ARF/p53 in lung cancer. |
| Mallakin A, Sugiyama T, Taneja P, Matise LA, Frazier DP, Choudhary M, Hawkins GA, D'Agostino RB Jr, Willingham MC, Inoue K. |
| Cancer Cell. 2007 Oct;12(4):381-94. |
| PMID 17936562 |
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| Repression of Dmp1 and Arf transcription by anthracyclins: critical roles of the NF-kappaB subunit p65. |
| Taneja P, Mallakin A, Matise LA, Frazier DP, Choudhary M, Inoue K. |
| Oncogene. 2007 Nov 22;26(53):7457-66. |
| PMID 17546045 |
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| Emerging roles of DMP1 in lung cancer. |
| Inoue K, Sugiyama T, Taneja P, Morgan RL, Frazier DP. |
| Cancer Res. 2008 Jun 15;68(12):4487-90. |
| PMID 18559489 |
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| Role of DMP1 and its future in lung cancer diagnostics. |
| Sugiyama T, Frazier DP, Taneja P, Morgan RL, Willingham MC, Inoue K. |
| Expert Rev Mol Diagn. 2008 Jul;8(4):435-47. |
| PMID 18598225 |
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| Oncogenic and non-oncogenic signaling pathways that regulate Dmp1 (Dmtf1). |
| Sugiyama T, Taneja P, Frazier DP, Kendig R, Morgan RL, Matise LA, Lagedrost SJ, Inoue K. |
| Clinical Medicine: Oncology. 2008 2, 1-11. |
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| The hDMP1 tumor suppressor is a new WT1 target in myeloid leukemias. |
| Tschan MP, Gullberg U, Shan D, Torbett BE, Fey MF, Tobler A. |
| Leukemia. 2008 May;22(5):1087-90. |
| PMID 17972942 |
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