Activated TNFa/NFkB Signaling Via Down Regulation of Faf1 in Asbestos-Induced Mesotheliomas from Arf Knock-out Mice

ABSTRACT: The human CDKN2A locus encodes two distinct proteins, p16(INK4A) and p14(ARF) [mouse p19(Arf)], designated INK4A and ARF herein, that are translated from alternatively spliced mRNAs. Human ARF is implicated as a tumor suppressor gene, mainly in association with the simultaneous deletion of INK4A. However, questions remain as to whether loss of ARF alone is sufficient to drive tumorigenesis. Here we report that mice deficient for Arf are susceptible to accelerated asbestos-induced malignant mesothelioma (MM). MMs arising in Arf (+/-) mice consistently exhibit biallelic inactivation of Arf, but unexpectedly, do not acquire additional recurrent genetic alterations that we previously identified in asbestos-induced MMs arising in Nf2 (+/-) mice. Array CGH analysis was used to detect a recurrent deletion at chromosome 4C6. A candidate in this region, Faf1 (FAS-associated factor 1), was further explored because it encodes a protein implicated in tumor cell survival and in the pathogenesis of some human tumor types. We confirmed hemizygous loss of Faf1 and down regulation of Faf1 protein in a series of MMs from Arf (+/-) mice, and then showed that Faf1 regulates TNFalpha-mediated NFkappaB signaling, a mechanism previously implicated in asbestos-induced oncogenesis of human mesothelial cells. Collectively, these investigations divulge important information regarding the significance of Arf inactivation in MM pathogenesis, and implicate Faf1 as a key component in the TNFalpha/NFkappaB signaling node that has now been independently implicated in the asbestos-induced oncogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE12419 | GEO | 2008/12/31

SECONDARY ACCESSION(S): PRJNA113115

REPOSITORIES: GEO