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.
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Acknowledgements
We thank Ms Karen Klein for critical reading of this review and Drs Bruce Torbett, Mario Tschan and Hiroshi Hirai for sharing unpublished data. We are very grateful to Drs Charles Sherr, Martine Roussel and John Cleveland for collaborative work and continuous encouragement on Dmp1 projects. We also thank Pankaj Taneja, Lauren Matise, Mark Willingham, Mayur Choudhary, Samantha Allen, Scott Barton, Asif Chaudhry and Ramesh Sreeramaneni for collaboration. K Inoue is supported by NIH/NCI 5R01CA106314.
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