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

Abstract

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 approximately 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 hDMP1 gene was detectable in approximately 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.

Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion

“…This result is opposite to that seen in Bmi1-null neural tissue where p16, not p19 ARF , is more significantly up-regulated (10). In ES cells, mutant K-ras causes up-regulation of p19 ARF , and Arf overexpression has been reported in latent K-ras G12D -induced lung tumors (30,31). Bmi1 overexpression contributes to Ras-induced transformation in culture and in vivo (6,32).…”

Regulation of murine hematopoietic stem cell quiescence by Dmtf1

“…28 In addition, Dmtf1 is deleted in approximately 40% of mouse models of lung cancers, and the hDmtf1 deletion can be demonstrated in approximately 35% of human lung cancer cells, particularly when the Arf and/or p53 locus is retained. 27 These observations suggest that Dmtf1 is a physiologic regulator of the Arf/p53 pathway, whereas in some cases, it imparts a growth-suppression effect in p53-deficient lung cancer cells. 27 Based on these findings, we hypothesized that Dmtf1 may play a role in HSC self-renewal similar to the previously reported involvement of p53 in HSC quiescence.…”

“…25 Given that the deletion or mutation of Arf or p53 is rare in tumors from Dmtf1 Ϫ/Ϫ mice, Dmtf1 may be a physiologic regulator of the Arf-p53 pathway. 26 Moreover, deletion of Dmtf1 is found in human lung cancer cells 27 and some leukemia cells. 27,28 The Dmtf1 promoter is activated by growth-promoting signals via the Ras/Raf/MEK/ ERK pathway, and the induction of Arf by Ras is Dmtf1 dependent.…”

“…26 Moreover, deletion of Dmtf1 is found in human lung cancer cells 27 and some leukemia cells. 27,28 The Dmtf1 promoter is activated by growth-promoting signals via the Ras/Raf/MEK/ ERK pathway, and the induction of Arf by Ras is Dmtf1 dependent. 23 Although it is generally believed that induction of Arf is Dmtf1 dependent, 29 other targets for Dmtf1 remain unknown in hematopoietic cells, especially lymphocytes.…”

Molecular and Genetic Aspects of Lung Cancer

“…the DMP1 gene normally works to suppress tumor formation and is non-functional in about 35 % of human lung cancers. According to earlier studies in mice, the gene is involved in activating the tumor suppressors p53 and Arf (51). When the DMP1 gene is not functional, these tumor suppressors are probably not available to stop tumor growth by killing cancer cells (38).…”