Dmp1 and tumor suppression

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.

Figure 1

The structure of the Dmp1 (Dmtf1) transcription factor. Both murine and human Dmp1 has three tandem myb-like repeats with two transactivation domains. Mutation of the lysine residue into glutamic acid abolishes its DNA binding. The cyclin Dinteraction domain has been mapped to the amino-terminal segment of the DNA-binding domain. The negative regulatory domain (NR) that is found in c-Myb has not been identified in Dmp1.

Figure 2

Disruption of the Arf-Mdm2-p53 pathway in Eμ-Myc lymphomas. In Dmp1^+/− and Dmp1^−/− Eμ-Myc lymphomas, there is a striking reduction in the frequencies of p53 mutations and Arf deletions. This suggests that Dmp1 is a regulator of the Arf-p53 pathway in vivo.

Figure 3

Dmp1 links the Rb and p53 pathways. The novel ‘Jun-Dmp1’ pathway links oncogenic Ras-Raf signaling and the Arf-p53 pathway. This pathway is independent of the classical cyclin D1/Cdk4-Rb-E2F signaling. E2Fs directly bind to the Dmp1 promoter and causes repression; thus they have differential effects on the Dmp1 and on the Arf promoter. Overexpression of D-cyclins inhibits the activity of Dmp1 in a Cdk-independent fashion; however, on the Arf promoter, Dmp1 and cyclin D1 act synergistically, and this activity is dependent on Cdks. Dmp1 might have other targets than Arf, especially in T lymphocytes.