Alternative titles; symbols
HGNC Approved Gene Symbol: DMTF1
Cytogenetic location: 7q21.12 Genomic coordinates (GRCh38) : 7:87,152,453-87,196,325 (from NCBI)
Using mouse cyclin D2 (123833) as bait in a yeast 2-hybrid screen, Hirai and Sherr (1996) cloned mouse Dmp1 from a T-lymphoma cDNA library. Dmp1 contains 3 central imperfect Myb (189990) repeats, indicating that it functions as a transcription factor. Dmp1 was expressed in quiescent cells, and was expressed uniformly throughout the cell cycle in synchronized macrophages and fibroblasts.
By searching an EST database for sequences similar to mouse Dmp1, Bodner et al. (1999) identified an EST containing human DMP1. The deduced 761-amino acid protein shares 95% identity with mouse Dmp1, with 100% identity through the Myb-like repeat regions. Northern blot analysis detected ubiquitous expression of a 4.4-kb transcript and weak expression of a 7.0-kb transcript. Expression was most prominent in testis, with decreasing levels in blood leukocytes, thymus, and spleen. Expression was also found throughout the brain, with the highest level in the substantia nigra.
By PCR of a myeloid leukemia cell line, Tschan et al. (2003) identified 3 distinct isoforms of DMP1. The longest variant, which they designated DMP1-alpha, encodes the full-length protein with a calculated molecular mass of 128 kD. This variant contains an N-terminal transactivation domain followed by a cyclin D-binding site, Myb homology regions, and a C-terminal transactivation domain. DMP1-beta and DMP1-gamma, formed by alternative splicing in intron 9, encode deduced proteins of 272 and 285 amino acids, with calculated molecular masses of 31 and 32 kD, respectively. These variants are identical to DMP1-alpha for the first 237 amino acids, then show unique C termini with disrupted Myb homology regions. PCR analysis detected expression of all 3 variants in all hematopoietic lineages evaluated. Distinct patterns of DMP1-alpha and DMP1-beta were detected in freshly isolated CD34 (142230)-positive cord blood progenitor cells and peripheral blood mononuclear cells.
Hirai and Sherr (1996) determined that mouse Dmp1 bound to the DNA consensus sequences CCCG(G/T)ATGT to activate transcription. Dmp1 bound to D-type cyclins directly in vitro and when coexpressed in insect cells. In both settings, Dmp1 was phosphorylated by cyclin D-dependent kinases (see CDK4, 123829).
Inoue and Sherr (1998) found that the introduction of mouse Dmp1 into a mouse fibroblast cell line inhibited entry into S phase. Cell cycle arrest depended upon the ability of Dmp1 to bind to DNA and to transactivate gene expression. Cell cycle arrest was antagonized by coexpression of D-type cyclins, including a cyclin D1 (168461) point mutant that does not bind to CDK4.
Bodner et al. (1999) analyzed leukemic interphase blast cells showing abnormalities of chromosome 7, including 6 cases of acute myelogenous leukemia, 2 cases of acute lymphoblastic leukemia, and 1 case of chronic myeloid leukemia (608232). In 7 of these cases, most cells examined contained a single copy of the DMP1 gene. The remaining 2 cases showed monosomy for chromosome 7 (252270), leading to a single copy of the DMP1 gene.
Using an ANPEP (151530) promoter-reporter construct, Tschan et al. (2003) determined that DMP1-alpha, but not DMP1-beta or DMP1-gamma, could activate transcription. Furthermore, DMP1-beta inhibited ANPEP promoter transactivation by DMP1-alpha. Stable, ectopic expression of DMP1-beta and to a lesser extent DMP1-gamma reduced endogenous cell surface levels of ANPEP in the human monocytoma cell line U937. Stable, ectopic expression of DMP1-beta also altered phorbol ester-induced terminal differentiation of U937 cells to macrophages and resulted in maintenance of proliferation.
Tschan et al. (2003) determined that the DMTF1 gene contains 18 exons, with 3 alternative exon 10 sequences utilized by 3 DMTF1 isoforms. The gene spans about 44 kb. The first intron spans about 11 kb, and the translation start site is located in exon 3.
By FISH, Bodner et al. (1999) mapped the DMTF1 gene to chromosome 7q21.
Inoue et al. (2001) found that Dmp1-null mice spontaneously developed lethal tumors in their second year of life with a mean latency of 83 weeks. In their first year of life, mutant mice showed heightened susceptibility to carcinogen- and radiation-induced tumors.
Bodner, S. M., Naeve, C. W., Rakestraw, K. M., Jones, B. G., Valentine, V. A., Valentine, M. B., Luthardt, F. W., Willman, C. L., Raimondi, S. C., Downing, J. R., Roussel, M. F., Sherr, C. J., Look, A. T. Cloning and chromosomal localization of the gene encoding human cyclin D-binding Myb-like protein (hDMP1). Gene 229: 223-228, 1999. [PubMed: 10095122] [Full Text: https://doi.org/10.1016/s0378-1119(98)00591-5]
Hirai, H., Sherr, C. J. Interaction of D-type cyclins with a novel myb-like transcription factor, DMP1. Molec. Cell. Biol. 16: 6457-6467, 1996. [PubMed: 8887674] [Full Text: https://doi.org/10.1128/MCB.16.11.6457]
Inoue, K., Sherr, C. J. Gene expression and cell cycle arrest mediated by transcription factor DMP1 is antagonized by D-type cyclins through a cyclin-dependent-kinase-independent mechanism. Molec. Cell. Biol. 18: 1590-1600, 1998. [PubMed: 9488476] [Full Text: https://doi.org/10.1128/MCB.18.3.1590]
Inoue, K., Zindy, F., Randle, D. H., Rehg, J. E., Sherr, C. J. Dmp1 is haplo-insufficient for tumor suppression and modifies the frequencies of Arf and p53 mutations in Myc-induced lymphomas. Genes Dev. 15: 2934-2939, 2001. [PubMed: 11711428] [Full Text: https://doi.org/10.1101/gad.929901]
Tschan, M. P., Fischer, K. M., Fung, V. S., Pirnia, F., Borner, M. M., Fey, M. F., Tobler, A., Torbett, B. E. Alternative splicing of the human cyclin D-binding Myb-like protein (hDMP1) yields a truncated protein isoform that alters macrophage differentiation patterns. J. Biol. Chem. 278: 42750-42760, 2003. [PubMed: 12917399] [Full Text: https://doi.org/10.1074/jbc.M307067200]