DMTF1 (cyclin D binding myb-like transcription factor 1)

2008-11-01   Kazushi Inoue 

Dept. of Pathology, Wake Forest University Health Sciences, 2102 Gray Building, Medical Center Boulevard, Winston-Salem, NC 27157-0001, USA

Identity

HGNC
LOCATION
7q21.12
LOCUSID
ALIAS
DMP1,DMTF,MRUL,hDMP1
FUSION GENES

DNA/RNA

Note

There are at least three splicing variants for hDMTF1 alpha, beta and gamma.
Atlas Image
The human DMTF1 genomic locus. DMTF1 consists of 20 exons and a gene named MGC4175 is localized at its 3 end in a reverse orientation.

Description

20 Exons.

Transcription

Major transcript: 3.9kb (human) (and 3.75kb in the mouse).

Pseudogene

In mus musculus, the pseudogene of Dmtf1 exists on chromosome XE3.
NT 039716, gi:149272292.

Proteins

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.
Atlas Image
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.

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)

Mutations

Note

Point mutations for human DMTF1 in human cancer or other human disorders have not been reported.
Promoter hypermethylation for the hDMTF1 promoter is very rare ( around 2%) in human non-small-cell lung carcinomas.
Single nucleotide polymorphisms for hDMTF1 are shown in http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=9988.

Germinal

N/A.

Somatic

N/A.

Implicated in

Entity name
Non-small-cell lung carcinoma
Disease
One report shows that loss of heterozygosity (LOH) for the human DMTF1 gene was found in around 35 % of human non-small-cell lung cancers, especially those without deletions or methylation of p14ARF and/or mutations of p53. NSCLC with LOH for hDMTF1 showed significantly weaker nuclear staining for DMTF1 protein than tumors without LOH.
Prognosis
The correlation between LOH for hDMTF1 and the prognoses of non-small-cell lung cancer patients has not been reported.
Hybrid gene
Not reported.
Fusion protein
Not reported.
Oncogenesis
N/A
Entity name
Hematopoietic malignancies involving chromosome del(7q)
Prognosis
The prognoses of human leukemias with del(7q) abnormalities are generally poor.
Cytogenetics
One allele of the hDMTF1 locus was deleted in 9 of 9 leukemic cells with chromosome 7q abnormalities by FISH analysis, regardless of the detailed karyotype at 7q, suggesting that mono-allelic loss of hDMTF1 could contribute to 7q- leukemias.
Hybrid gene
Not reported.
Fusion protein
Not reported.
Oncogenesis
N/A

Bibliography

Pubmed IDLast YearTitleAuthors
100951221999Cloning and chromosomal localization of the gene encoding human cyclin D-binding Myb-like protein (hDMP1).Bodner SM et al
88876741996Interaction of D-type cyclins with a novel myb-like transcription factor, DMP1.Hirai H et al
172378162007Dmp1 and tumor suppression.Inoue K et al
100971511999Induction of ARF tumor suppressor gene expression and cell cycle arrest by transcription factor DMP1.Inoue K et al
97869291998Regulation of the CD13/aminopeptidase N gene by DMP1, a transcription factor antagonized by D-type cyclins.Inoue K et al
185594892008Emerging roles of DMP1 in lung cancer.Inoue K et al
108987942000Disruption of the ARF transcriptional activator DMP1 facilitates cell immortalization, Ras transformation, and tumorigenesis.Inoue K et al
117114282001Dmp1 is haplo-insufficient for tumor suppression and modifies the frequencies of Arf and p53 mutations in Myc-induced lymphomas.Inoue K et al
179365622007Mutually exclusive inactivation of DMP1 and ARF/p53 in lung cancer.Mallakin A et al
156018442005Ras-Raf-Arf signaling critically depends on the Dmp1 transcription factor.Sreeramaneni R et al
175460452007Repression of Dmp1 and Arf transcription by anthracyclins: critical roles of the NF-kappaB subunit p65.Taneja P et al
129173992003Alternative splicing of the human cyclin D-binding Myb-like protein (hDMP1) yields a truncated protein isoform that alters macrophage differentiation patterns.Tschan MP et al
179729422008The hDMP1 tumor suppressor is a new WT1 target in myeloid leukemias.Tschan MP et al

Other Information

Locus ID:

NCBI: 9988
MIM: 608491
HGNC: 14603
Ensembl: ENSG00000135164

Variants:

dbSNP: 9988
ClinVar: 9988
TCGA: ENSG00000135164
COSMIC: DMTF1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000135164ENST00000331242Q9Y222
ENSG00000135164ENST00000394703Q9Y222
ENSG00000135164ENST00000412139Q9Y222
ENSG00000135164ENST00000413276E7EPA0
ENSG00000135164ENST00000414630C9J4F7
ENSG00000135164ENST00000420131A0A1D5RMP8
ENSG00000135164ENST00000423590C9JLR5
ENSG00000135164ENST00000425406Q9Y222
ENSG00000135164ENST00000425705C9JFR2
ENSG00000135164ENST00000428819C9K0K9
ENSG00000135164ENST00000430405C9JGT5
ENSG00000135164ENST00000432366C9JED5
ENSG00000135164ENST00000432937Q9Y222
ENSG00000135164ENST00000434534C9JVQ7
ENSG00000135164ENST00000446796C9K0L9
ENSG00000135164ENST00000447863Q9Y222
ENSG00000135164ENST00000448598C9J4F7
ENSG00000135164ENST00000449088C9JZZ6
ENSG00000135164ENST00000453049C9J8Y5
ENSG00000135164ENST00000454008H7C388
ENSG00000135164ENST00000547146F8VXY9
ENSG00000135164ENST00000579592J3QLW3
ENSG00000135164ENST00000579677Q9Y222
ENSG00000135164ENST00000579850J3QLN9
ENSG00000135164ENST00000582204J3QKU5
ENSG00000135164ENST00000582925J3KRC1
ENSG00000135164ENST00000584619Q9Y222

Expression (GTEx)

0
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Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
203517152011Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder.52
179365622007Mutually exclusive inactivation of DMP1 and ARF/p53 in lung cancer.43
129173992003Alternative splicing of the human cyclin D-binding Myb-like protein (hDMP1) yields a truncated protein isoform that alters macrophage differentiation patterns.34
150108952004Single nucleotide polymorphisms in breast cancer.26
230452802013Prognostic value of the hDMP1-ARF-Hdm2-p53 pathway in breast cancer.25
239383232013Cooperation between Dmp1 loss and cyclin D1 overexpression in breast cancer.24
223314602012Dmp1 physically interacts with p53 and positively regulates p53's stability, nuclear localization, and function.23
259658242015MicroRNA-155 promotes bladder cancer growth by repressing the tumor suppressor DMTF1.22
261870042015Human DMTF1β antagonizes DMTF1α regulation of the p14(ARF) tumor suppressor and promotes cellular proliferation.13
282570902017From General Aberrant Alternative Splicing in Cancers and Its Therapeutic Application to the Discovery of an Oncogenic DMTF1 Isoform.7

Citation

Kazushi Inoue

DMTF1 (cyclin D binding myb-like transcription factor 1)

Atlas Genet Cytogenet Oncol Haematol. 2008-11-01

Online version: http://atlasgeneticsoncology.org/gene/40340/dmtf1-(cyclin-d-binding-myb-like-transcription-factor-1)