Linking Nucleoporins, Mitosis, and Colon Cancer

Abstract

Suppression of a nuclear pore protein Nup358/RanBP2 is linked to mitotic cell death, but the clinical relevance of this link is unknown. In a recent issue of Cell, Vecchione et al. (2016) show that in approximately 10% of BRAF-like colorectal cancer (CC) patients, Nup358/RanBP2 is critical for survival. Treatment with vinorelbine, a microtubule-depolymerizing drug that inhibits mitosis, might be a potential treatment for these CCs.

Figure 1. From Nucleoporins to Colon Cancer, Via Mitosis

(A)A schematic representation of the nuclear pore complex structure Nup358/RanBP2 is colored in red (left). The current mammalian nuclear pore proteins/nucleoporins are Nup358/RanBP2, Nup214, Nup88, NupL2, Gle1, Aladin, Nup62, Nup54, Nup58, Rae1, Nup98, Nup133, Nup160, Nup85, Nup107, Nup96, Seh1, Sec13, ELYS, Nup43, Nup37, Gp210, Ndc1, TMEM33, Pom121, Nup205, Nup188, Nup93, Nup155, Nup35, Tpr, Nup153, and Nup50. The domain organization of full-length human Nup358/RanBP2 is shown on the right. Numbers on the right refer to amino acids. Vertical lines are FG-motifs; Leu-rich, leucine-rich domain; R, Ran-binding domain; E3, E3 ligase domain; Zinc Fingers, zinc finger motifs; and CY, cyclophilin homology domain. (B) Asimplified timeline for sporadic colorectal cancer (CRC) pathogenesis.Tumorigenesis can be divided into tumor initiation (development of an adenoma) and tumor progression to malignancy (carcinoma) that can spread as metastasis. BRAF (V600E) is colored in brown. (C)A Model for Nup358/RanBP2 in mitotic progression and faithful chromosomal segregation. The absence of RanBP2/Nup358 during mitosis or vinorelbine treatments causes abnormal mitotic spindles, supernumerary centrosomes, and impaired chromosomal alignment and induces mitotic catastrophe and cell death.