Takayuki Sugiyama^1,2, Donna P. Frazier^1,2, Pankaj Taneja^1,2, Robert D. Kendig^1,2, Rachel L. Morgan^1,2, Lauren A. Matise^1,2, Sarah J. Lagedrost^1,2 and Kazushi Inoue^1,2

¹The Departments of Pathology, ²Cancer Biology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, N.C. 27157-0001, U.S.A.

Abstract

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 (hDMP1) 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, hDMP1 is clearly involved in human carcinogenesis, and tumors with hDMP1 deletion may constitute a discrete disease entity.