Mutually Exclusive Inactivation of DMP1 and ARF/p53 in Lung Cancer

Summary Dmp1 (Dmtf1) is activated by oncogenic Ras-Raf signaling and induces cell-cycle arrest in an Arf, p53-dependent fashion. The survival of K-ras LA mice was shortened by ∼15 weeks in both Dmp1 +/− and Dmp1 −/− backgrounds, the lung tumors of which showed significantly decreased frequency of p53 mutations compared to Dmp1 +/+ . Approximately 40% of K-ras LA lung tumors from Dmp1 +/+ mice lost one allele of the Dmp1 gene, suggesting the primary involvement of Dmp1 in K-ras -induced tumorigenesis. Loss of heterozygosity (LOH) of the h DMP1 gene was detectable in ∼35% of human lung carcinomas, which was found in mutually exclusive fashion with LOH of INK4a/ARF or that of P53 . Thus, DMP1 is a pivotal tumor suppressor for both human and murine lung cancers.