Signal Transduction Involving the Dmp1 Transcription Factor and its Alteration in Human Cancer

Abstract

Summary Dmp1 (cyclin D-interacting myb-like protein 1; also called Dmtf1) is a transcription factor that has been isolated in a yeast two-hybrid screen through its binding property to cyclin D2. Dmp1 directly binds to and activates the Arf promoter and induces Arf-p53-dependent cell cycle arrest in primary cells. D-type cyclins usually inhibit Dmp1-mediated transcription in a Cdk-independent fashion; however, Dmp1 shows synergistic effects with D-cyclins on the Arf promoter. Ras or Myc oncogene-induced tumor formation is accelerated in both Dmp1 +/- and Dmp1 -/- mice with no significant differences between Dmp1 +/- and Dmp1 -/- . Thus, Dmp1 is haplo-insufficient for tumor suppression. Tumors from Dmp1 -/- or Dmp1 +/- mice often retain wild-type Arf and p53 , suggesting that Dmp1 is a physiological regulator of the Arf-p53 pathway. The Dmp1 promoter is activated by oncogenic Ras-Raf signaling, while it is repressed by physiological mitogenic stimuli, overexpression of E2F proteins, and genotoxic stimuli mediated by NF-κB. The human DMP1 gene (h DMP1 ) is located on chromosome 7q21 and is hemizygously deleted in approximately 40% of human lung cancers, especially those that retain normal INK4a/ARF and P53 loci. Thus, h DMP1 is clearly involved in human carcinogenesis, and tumors with h DMP1 deletion may constitute a discrete disease entity.