Nuclear size is sensitive to NTF2 protein levels dependent on Ran binding

Abstract

Altered nuclear size is associated with many cancers, and determining if cancer-associated changes in nuclear size contribute to carcinogenesis necessitates an understanding of mechanisms of nuclear size regulation. While nuclear import rates generally positively correlate with nuclear size, NTF2 levels negatively affect nuclear size, despite NTF2's role in nuclear recycling of the import factor Ran. We show that binding of Ran to NTF2 is required for NTF2 to inhibit nuclear expansion and import of large cargo molecules in Xenopus laevis egg and embryo extracts, consistent with our observation that NTF2 reduces the diameter of the NPC in a Ran binding dependent manner. Furthermore, we demonstrate that ectopic NTF2 expression in Xenopus embryos and mammalian tissue culture cells alters nuclear size. Lastly, increases in nuclear size during melanoma progression correlate with reduced NTF2 expression, and increasing NTF2 levels in melanoma cells is sufficient to reduce nuclear size. These results show a conserved capacity for NTF2 to impact nuclear size, and we propose that NTF2 may be a novel cancer biomarker.