Expression of Dmp1 in Specific Differentiated, Nonproliferating Cells and Its Regulation by E2Fs

Dmp1 is a Myb-like transcription factor that transmits oncogenic Ras-Raf signaling to the Arf-p53 pathway and induces cell cycle arrest. Immunohistochemical staining was performed to identify the pattern of Dmp1 expression in normal murine tissues compared with the proliferation marker, Ki67. In thymus, the nuclei of mature T lymphocytes in the medulla were strongly positive for Dmp1, whereas Ki67 was detected only in the cortex. In intestine, Dmp1 was detected in the nuclei of superficial layers of the villi, whereas Ki67-positive cells were confined to the lower one-third of the crypt. Double staining for Dmp1 and Ki67 revealed that these two proteins were expressed in mutually exclusive fashion in nearly all the tissues examined. Subsets of E2Fs were specifically bound to the Dmp1 promoter upon mitogenic signaling and E2Fs 1-4 inhibited the Dmp1 promoter in a reporter assay. The Dmp1 promoter was repressed when the cells entered the S to G2/M phase of the cell cycle when both Dmp1 and Arf expressions were downregulated. The Dmp1 mRNA was not downregulated by serum in E2F-DB(+) cells, suggesting that the Dmp1 promoter repression is E2F-dependent. This explains why the Dmp1 and Ki67-positive cells are stained in mutually exclusive fashion in normal tissues.