Mutually exclusive inactivation of DMP1 and ARF/p53 in lung cancer

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 similar to 15 weeks in both Dmp 1(+1)and Dmpl(-1-) backgrounds, the lung tumors of which showed significantly decreased frequency of p53 mutations compared to Dmpl(+/+). Approximately 40% of K-ras(LA) lung tumors from Dmpl(+/+) 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 hDMP1 gene was detectable in similar to 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.