ABSTRACT
The Ter mutation in Dead-End 1 (Dnd1), Dnd1Ter, which leads to a premature stop codon, has been determined to be the cause for primordial germ cell deficiency, accompanied with a high incidence of congenital testicular germ cell tumors (TGCTs) or teratomas in the 129/Sv-Ter mice. As an RNA-binding protein, DND1 can bind the 3'-untranslated region (3'-UTR) of mRNAs and function in translational regulation. DND1 can block microRNA (miRNA) access to the 3'-UTR of target mRNAs, thus inhibiting miRNA-mediated mRNA degradation and up-regulating translation or can also function to degrade or repress mRNAs. Other mechanisms of DND1 activity include promoting translation initiation and modifying target protein activity. Although Dnd1Ter mutation causes spontaneous TGCT only in male 129 mice, it can also cause ovarian teratomas in mice when combined with other genetic defects or cause germ cell teratomas in both genders in the WKY/Ztm rat strain. Furthermore, studies on human cell lines, patient cancer tissues, and the use of human cancer genome analysis indicate that DND1 may possess either tumor-suppressive or -promoting functions in a variety of somatic cancers. Here we review the involvement of DND1 in cancers, including what appears to be its emerging role in somatic cancers.
ABSTRACT
BACKGROUND: Splicing factor 1 (SF1) is a conserved alternative splicing factor expressed in many different mammalian cell types. The genetically modified Sf1+/- (or Sf1ß-geo/+) mice express reduced levels of SF1 protein in mouse tissues, including in cells of the intestines. Mutational inactivation of human adenomatous polyposis coli (APC) gene deregulates the Wnt signaling pathway and is a frequent genetic event in colon cancers. Mice with a point mutation in the Apc gene (ApcMin/+) also develop numerous intestinal polyps at a young age. Our aim was to determine the effect of reduced SF1 levels on polyp development due to the strong driver ApcMin/+ mutation. METHODS: We utilized mice genetically deficient for expression of SF1 to assess how SF1 levels affect intestinal tumorigenesis. We crossed ApcMin/+ to Sf1+/- mice to generate a cohort of heterozygous mutant ApcMin/+;Sf1+/- mice and compared intestinal polyp development in these mice to that in a control cohort of sibling ApcMin/+ mice. We compared total polyp numbers, sizes of polyps and gender differences in polyp numbers between ApcMin/+;Sf1+/- and ApcMin/+ mice. RESULTS: Our results showed that ApcMin/+ mice with lower SF1 expression developed 25-30% fewer intestinal polyps compared to their ApcMin/+ siblings with normal SF1 levels. Interestingly, this difference was most significant for females (ApcMin/+;Sf1+/- and ApcMin/+ females developed 39 and 55 median number of polyps, respectively). Furthermore, the difference in polyp numbers between ApcMin/+;Sf1+/- and ApcMin/+ mice was significant for smaller polyps with a size of 2 mm or less, whereas both groups developed similar numbers of larger polyps. CONCLUSIONS: Our results suggest that lower SF1 levels likely inhibit the rate of initiation of polyp development due to ApcMin/+ driver mutation in the mouse intestine. Thus, therapeutic lowering of SF1 levels in the intestine could attenuate intestinal polyp development.
