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Published on: January 7, 2019
Dmp1 and tumor suppression
K Inoue1, A Mallakin, D P Frazier
1Department of Pathology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157-0001, USA. kinoue@wfubmc.edu
Abstract:
Dmp1 (cyclin D binding myb-like protein 1; also called Dmtf1) is a transcription factor that was isolated in a yeast two-hybrid screen through its binding property to cyclin D2. Although it was initially predicted to be involved in the cyclin D-Rb pathway, overexpression of Dmp1 in primary cells induces cell cycle arrest in an Arf, p53-dependent fashion. Dmp1 is a unique Arf regulator, the promoter of which is activated by oncogenic Ras-Raf signaling. Dmp1 expression is repressed by physiological mitogenic stimuli as well as by overexpressed E2F proteins; thus, it is a novel marker of cells that have exited from the cell cycle. Spontaneous and oncogene-induced tumor formation is accelerated in both Dmp1(+/-) and Dmp1(-/-) mice; the Dmp1(+/-) tumors often retain and express the wild-type allele; thus, Dmp1 is haplo-insufficient for tumor suppression. Tumors from Dmp1(+/-) and Dmp1(-/-) mice often retain wild-type Arf and p53, suggesting that Dmp1 is a physiological regulator of the Arf-p53 pathway. The human DMP1 (hDMP1) gene is located on chromosome 7q21, the locus of which is often deleted in myeloid leukemia and also in some types of solid tumors. Post-translational modification of Dmp1 and its role in human malignancy remain to be investigated.
Insights
Cyclin D binding myb-like protein 1 (Dmp1) acts as a tumor suppressor by regulating the Arf-p53 pathway. Loss of Dmp1 accelerates tumor formation, highlighting its critical role in cell cycle control and cancer prevention.
Area of Science:
- Molecular Biology
- Cell Cycle Regulation
- Oncology
Background:
- Dmp1 (cyclin D binding myb-like protein 1) is a transcription factor identified via its interaction with cyclin D2.
- Initially thought to be involved in the cyclin D-Rb pathway, Dmp1's role extends to cell cycle arrest.
- Dmp1 is a novel regulator of Arf, with its promoter activated by oncogenic Ras-Raf signaling.
Purpose of the Study:
- To investigate the function of Dmp1 in cell cycle regulation and tumor suppression.
- To determine the relationship between Dmp1, Arf, and p53.
- To assess the role of Dmp1 in oncogenesis using mouse models.
Main Methods:
- Yeast two-hybrid screening to identify Dmp1 binding partners.
- Overexpression studies in primary cells to analyze cell cycle effects.
- Analysis of tumor formation in Dmp1 heterozygous and knockout mice.
- Examination of Arf and p53 status in Dmp1-deficient tumors.
Main Results:
- Dmp1 overexpression induces cell cycle arrest dependent on Arf and p53.
- Dmp1 expression is repressed by mitogenic stimuli and E2F, marking cells exiting the cell cycle.
- Dmp1 haploinsufficiency accelerates spontaneous and oncogene-induced tumor formation.
- Tumors in Dmp1-deficient mice often retain wild-type Arf and p53, confirming Dmp1's role as a physiological Arf-p53 pathway regulator.
Conclusions:
- Dmp1 is a critical tumor suppressor that functions through the Arf-p53 pathway.
- Dmp1 acts as a novel regulator of Arf, linking Ras-Raf signaling to cell cycle exit.
- The human DMP1 gene locus is implicated in myeloid leukemia and solid tumors, suggesting its relevance in human malignancy.
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