HHS Public Access Author manuscript Author Manuscript
Cell Chem Biol. Author manuscript; available in PMC 2017 May 08. Published in final edited form as: Cell Chem Biol. 2016 May 19; 23(5): 537–539. doi:10.1016/j.chembiol.2016.05.004.
Linking Nucleoporins, Mitosis, and Colon Cancer Richard W. Wong1,* and Maximiliano D’Angelo2,* 1Cell-Bionomics
Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Bio-AFM Frontier Research Center, and Laboratory of Molecular Cellular Biology, Kanazawa University, Kakuma-machi, Kanazawa 920–1192, Japan 2Development,
Author Manuscript
Aging, and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
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.
Author Manuscript
Nuclear pore complexes (NPC) are large protein channels that act as the sole mediators of molecular exchange between the nucleus and the cytoplasm of eukaryotic cells (Ibarra and Hetzer, 2015; Raices and D’Angelo, 2012). Notably, these giant structures (~110 MDa in humans) are composed of multiple copies of ~32 different proteins, termed nucleoporins or Nups (Figure 1A). Along with its function in controlling nucleocytoplasmic transport, the NPC and its components have been found to exert many transport-independent functions. One of the most studied transport-independent functions of Nups is their mitotic role. When NPCs disassemble during mitotic nuclear envelope breakdown, many soluble Nups relocate to kinetochores, mitotic spindles, and centrosomes (Ibarra and Hetzer, 2015). The findings that Nups are critical for the assembly and function of these structures and that they are required to ensure proper chromosome segregation indicate that Nups are vital for maintaining genome integrity, and suggests that alterations in their mitotic roles could contribute to cellular transformation and cancer development.
Author Manuscript
In a study consistent with this idea, Vecchione et al. (2016) provide new evidence for the importance of Nup mitotic functions in cancer development by showing that Nup358/ RanBP2, a Nup of the NPC cytoplasmic filaments, contributes to the survival of colon cancer (CC) cells by alleviating the mitotic defects associated with the BRAF(V600E) mutation. Nup358/RanBP2 is a crucial cytosolic component of the filaments that attach to the cytoplasmic ring of the NPC (Figure 1A). This large protein (3224 residues in humans) can
*
Correspondence: [email protected] (R.W.W.), [email protected] (M.D.), http://dx.doi.org/10.1016/ j.chembiol.2016.05.004.
Wong and D’Angelo
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Author Manuscript
be separated into several domains: an N-terminal TPR domain, an α-helical region, four Ran-binding domains, eight tandem zinc fingers, a SUMO E3 ligase domain, FG and FxFG repeats that act as binding surfaces for transport receptors, and a C-terminal domain that displays sequence homology to cyclophilins (Figure 1A). Because it binds to the small GTPase protein Ran and to nuclear transport receptors, Nup358/RanBP2 function was initially linked to nucleocytoplasmic transport; however, consistent with its multi-domain configuration, Nup358/RanBP2 has been shown to have more pleiotropic functions. This large Nup is now recognized as a regulator of numerous cellular processes (Hashizume et al., 2013). Together with Ran GTPase activating protein 1 (RanGAP1), Nup358/RanBP2 relocates to kinetochores and mitotic spindle microtubules during mitosis (Hashizume et al., 2013; Joseph et al., 2004; Salina et al., 2003) and Hashizume et al. (2013) previously discovered that its down-modulation induces G2/M phase arrest, impairs chromosomal alignment and results in mitotic catastrophe and cell death.
Author Manuscript
Interestingly, Nup358/RanBP2 has been associated with cancer in different, and possibly contradicting, manners. On one hand, Nup358/RanBP2 was described to act as a tumor suppressor for its role in preventing chromosome segregation errors and because mice with decreased levels of this nucleoporin are highly sensitive to tumor formation (Dawlaty et al., 2008). On the other hand, Nup358/RanBP2 participation in chromosomal translocations that result in hematological malignancies suggest a potential oncogenic role (Nofrini et al., 2016). Vecchione et al. (2016) now discover that increased expression of Nup358/RanBP2 protects a subgroup of colorectal cancer (CRC) cells from undergoing mitotic cell death, which is consistent with an oncogenic function.
Author Manuscript Author Manuscript
CRC is the third most common cancer worldwide, resulting in over 600,000 deaths per year. In the US alone, CRC is predicted to exceed 17 billion US dollars in medical care costs by the year 2020 (Mariotto et al., 2011). The majority of CRC cases are sporadic, with no clear hereditary connection. The development of CRC is a multistep process whereby normal colon epithelial cells develop into colorectal adenoma (polyps) and, over time, can give rise to colorectal adenocarcinoma (Carethers and Jung, 2015; Popovici et al., 2012) (Figure 1B). Vecchione et al. (2016) studied an important subset of CCs that carry the BRAF mutation V600E; this mutation occurs in about 8%–10% of CRC patients and is associated with a poor prognosis, particularly in the metastatic setting (Popovici et al., 2012). BRAF(V600E) carrying CCs have a particular gene expression pattern that allows for the identification of tumors having this mutation with extremely high sensitivity. This gene expression pattern, known as the “BRAF-like” signature, also identifies a subset of KRAS mutants and wildtype tumors with similarly poor prognoses (Popovici et al., 2012). To uncover potential vulnerabilities in BRAF(V600E) tumors that could be exploited therapeutically, the group identified a group of genes that are differentially overexpressed in CRC and studied their role in the survival of CC cells using loss-of-function genetic approaches. Vecchione et al. (2016) discovered that suppression of Nup358/RanBP2 is selectively lethal to colon cancers having the BRAF-like signature. Consistent with previous findings (Hashizume et al., 2013; Joseph et al., 2004; Salina et al., 2003), they found that depletion of Nup358/RanBP2 causes defective kinetochore structure and composition, abnormal mitotic progression, and abnormal chromosome segregation. BRAF-like CC cells depleted of Nup358/RanBP2 showed prolonged mitosis or mitotic arrest, which eventually triggered mitotic cell death. Cell Chem Biol. Author manuscript; available in PMC 2017 May 08.
Wong and D’Angelo
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Author Manuscript
These findings are in agreement with the previous studies in HeLa cells (Hashizume et al., 2013). Vecchione et al. (2016) also discovered that BRAF-like CC cell lines are defective in kinetochore microtubule outgrowth and that Nup358/RanBP2 depletion further potentiates this abnormality, leading to mitotic cell death (Figure 1C). This discovery allowed them to propose that BRAF-like CC cells depend on Nup358/RanBP2 expression to tolerate the mitotic defects in microtubule nucleation from kinetochores.
Author Manuscript
The specific defect of BRAF-like cells in microtubule formation revealed a potential susceptibility of such tumors to microtubule disrupting agents. To investigate this hypothesis, Vecchione et al. (2016) tested the effect of vinorelbine, a chemotherapy medication that is mainly used for the treatment of breast and non-small cell lung cancers, on CC cell survival. Strikingly, they found that BRAF-like CC cells were 10-to 10,000-fold more sensitive to vinorelbine than non-BRAF-like cells. Using xenograft models, the authors showed that the growth of tumors derived from BRAF-like cells, but not from non-BRAFlike cells, was also inhibited by the microtubule-depolymerizing drug. Moreover, they identified that BRAF-like cells implanted into liver responded positively to vinorelbine treatment, suggesting that metastatic tumors derived from cells with the BRAF-like signature could potentially be treated with mitotic drugs. Taking all these data into consideration, the authors proposed that BRAF(V600E) could be used to predict the tumor response to DM4, a cytotoxic agent that shares a common mechanism of action to vinblastine. Using PDX models, they demonstrated that 44% of DM4 PDX responders, but none of the non-responders, carried the BRAF(V600E) mutation, supporting the authors’ hypothesis that targeting microtubule dynamics could represent a specific therapy for the treatment of BRAF-like tumors.
Author Manuscript
This work by Vecchione et al. (2016) is exciting not only because it provides evidence on how CC defend themselves from mitotic cell death, but also because it exposes a potential therapeutic pathway for the treatment of a significant percentage of CRCs with anti-mitotic drugs already approved by the FDA. As proposed by the authors, a clinical trial to assess the utility of vinorelbine in BRAF-like colon cancer is likely to follow in the near future. Finally, Nup358/RanBP2 is only one of at least ten Nups that relocate to centrosomes, spindles, and/or kinetochores during mitosis (Ibarra and Hetzer, 2015). Understanding the mitotic functions of specific Nups and dissecting their contribution to pathogenesis will likely uncover additional targets for the treatment of NPC-related diseases.
References Author Manuscript
Carethers JM, Jung BH. Gastroenterology. 2015; 149:1177–1190.e3. [PubMed: 26216840] Dawlaty MM, Malureanu L, Jeganathan KB, Kao E, Sustmann C, Tahk S, Shuai K, Grosschedl R, van Deursen JM. Cell. 2008; 133:103–115. [PubMed: 18394993] Hashizume C, Kobayashi A, Wong RW. Cell Death Dis. 2013; 4:e854. [PubMed: 24113188] Ibarra A, Hetzer MW. Genes Dev. 2015; 29:337–349. [PubMed: 25691464] Joseph J, Liu ST, Jablonski SA, Yen TJ, Dasso M. Curr Biol. 2004; 14:611–617. [PubMed: 15062103] Mariotto AB, Yabroff KR, Shao Y, Feuer EJ, Brown ML. J Natl Cancer Inst. 2011; 103:117–128. [PubMed: 21228314]
Cell Chem Biol. Author manuscript; available in PMC 2017 May 08.
Wong and D’Angelo
Page 4
Author Manuscript
Nofrini, V., Di Giacomo, D., Mecucci, C. Eur J Hum Genet. 2016. http://dx.doi.org/10.1038/ejhg. 2016.25 Popovici V, Budinska E, Tejpar S, Weinrich S, Estrella H, Hodgson G, Van Cutsem E, Xie T, Bosman FT, Roth AD, Delorenzi M. J Clin Oncol. 2012; 30:1288–1295. [PubMed: 22393095] Raices M, D’Angelo MA. Nat Rev Mol Cell Biol. 2012; 13:687–699. [PubMed: 23090414] Salina D, Enarson P, Rattner JB, Burke B. J Cell Biol. 2003; 162:991–1001. [PubMed: 12963708] Vecchione L, Gambino V, Raaijmakers J, Schlicker A, Fumagalli A, Russo M, Villanueva A, Beerling E, Bartolini A, Mollevi DG, et al. Cell. 2016; 165:317–330. [PubMed: 27058664]
Author Manuscript Author Manuscript Author Manuscript Cell Chem Biol. Author manuscript; available in PMC 2017 May 08.
Wong and D’Angelo
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Author Manuscript Author Manuscript Figure 1. From Nucleoporins to Colon Cancer, Via Mitosis
Author Manuscript
(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.
Author Manuscript Cell Chem Biol. Author manuscript; available in PMC 2017 May 08.
Cell Chem Biol. Author manuscript; available in PMC 2017 May 08. Published in final edited form as: Cell Chem Biol. 2016 May 19; 23(5): 537–539. doi:10.1016/j.chembiol.2016.05.004.
Linking Nucleoporins, Mitosis, and Colon Cancer Richard W. Wong1,* and Maximiliano D’Angelo2,* 1Cell-Bionomics
Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Bio-AFM Frontier Research Center, and Laboratory of Molecular Cellular Biology, Kanazawa University, Kakuma-machi, Kanazawa 920–1192, Japan 2Development,
Author Manuscript
Aging, and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
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.
Author Manuscript
Nuclear pore complexes (NPC) are large protein channels that act as the sole mediators of molecular exchange between the nucleus and the cytoplasm of eukaryotic cells (Ibarra and Hetzer, 2015; Raices and D’Angelo, 2012). Notably, these giant structures (~110 MDa in humans) are composed of multiple copies of ~32 different proteins, termed nucleoporins or Nups (Figure 1A). Along with its function in controlling nucleocytoplasmic transport, the NPC and its components have been found to exert many transport-independent functions. One of the most studied transport-independent functions of Nups is their mitotic role. When NPCs disassemble during mitotic nuclear envelope breakdown, many soluble Nups relocate to kinetochores, mitotic spindles, and centrosomes (Ibarra and Hetzer, 2015). The findings that Nups are critical for the assembly and function of these structures and that they are required to ensure proper chromosome segregation indicate that Nups are vital for maintaining genome integrity, and suggests that alterations in their mitotic roles could contribute to cellular transformation and cancer development.
Author Manuscript
In a study consistent with this idea, Vecchione et al. (2016) provide new evidence for the importance of Nup mitotic functions in cancer development by showing that Nup358/ RanBP2, a Nup of the NPC cytoplasmic filaments, contributes to the survival of colon cancer (CC) cells by alleviating the mitotic defects associated with the BRAF(V600E) mutation. Nup358/RanBP2 is a crucial cytosolic component of the filaments that attach to the cytoplasmic ring of the NPC (Figure 1A). This large protein (3224 residues in humans) can
*
Correspondence: [email protected] (R.W.W.), [email protected] (M.D.), http://dx.doi.org/10.1016/ j.chembiol.2016.05.004.
Wong and D’Angelo
Page 2
Author Manuscript
be separated into several domains: an N-terminal TPR domain, an α-helical region, four Ran-binding domains, eight tandem zinc fingers, a SUMO E3 ligase domain, FG and FxFG repeats that act as binding surfaces for transport receptors, and a C-terminal domain that displays sequence homology to cyclophilins (Figure 1A). Because it binds to the small GTPase protein Ran and to nuclear transport receptors, Nup358/RanBP2 function was initially linked to nucleocytoplasmic transport; however, consistent with its multi-domain configuration, Nup358/RanBP2 has been shown to have more pleiotropic functions. This large Nup is now recognized as a regulator of numerous cellular processes (Hashizume et al., 2013). Together with Ran GTPase activating protein 1 (RanGAP1), Nup358/RanBP2 relocates to kinetochores and mitotic spindle microtubules during mitosis (Hashizume et al., 2013; Joseph et al., 2004; Salina et al., 2003) and Hashizume et al. (2013) previously discovered that its down-modulation induces G2/M phase arrest, impairs chromosomal alignment and results in mitotic catastrophe and cell death.
Author Manuscript
Interestingly, Nup358/RanBP2 has been associated with cancer in different, and possibly contradicting, manners. On one hand, Nup358/RanBP2 was described to act as a tumor suppressor for its role in preventing chromosome segregation errors and because mice with decreased levels of this nucleoporin are highly sensitive to tumor formation (Dawlaty et al., 2008). On the other hand, Nup358/RanBP2 participation in chromosomal translocations that result in hematological malignancies suggest a potential oncogenic role (Nofrini et al., 2016). Vecchione et al. (2016) now discover that increased expression of Nup358/RanBP2 protects a subgroup of colorectal cancer (CRC) cells from undergoing mitotic cell death, which is consistent with an oncogenic function.
Author Manuscript Author Manuscript
CRC is the third most common cancer worldwide, resulting in over 600,000 deaths per year. In the US alone, CRC is predicted to exceed 17 billion US dollars in medical care costs by the year 2020 (Mariotto et al., 2011). The majority of CRC cases are sporadic, with no clear hereditary connection. The development of CRC is a multistep process whereby normal colon epithelial cells develop into colorectal adenoma (polyps) and, over time, can give rise to colorectal adenocarcinoma (Carethers and Jung, 2015; Popovici et al., 2012) (Figure 1B). Vecchione et al. (2016) studied an important subset of CCs that carry the BRAF mutation V600E; this mutation occurs in about 8%–10% of CRC patients and is associated with a poor prognosis, particularly in the metastatic setting (Popovici et al., 2012). BRAF(V600E) carrying CCs have a particular gene expression pattern that allows for the identification of tumors having this mutation with extremely high sensitivity. This gene expression pattern, known as the “BRAF-like” signature, also identifies a subset of KRAS mutants and wildtype tumors with similarly poor prognoses (Popovici et al., 2012). To uncover potential vulnerabilities in BRAF(V600E) tumors that could be exploited therapeutically, the group identified a group of genes that are differentially overexpressed in CRC and studied their role in the survival of CC cells using loss-of-function genetic approaches. Vecchione et al. (2016) discovered that suppression of Nup358/RanBP2 is selectively lethal to colon cancers having the BRAF-like signature. Consistent with previous findings (Hashizume et al., 2013; Joseph et al., 2004; Salina et al., 2003), they found that depletion of Nup358/RanBP2 causes defective kinetochore structure and composition, abnormal mitotic progression, and abnormal chromosome segregation. BRAF-like CC cells depleted of Nup358/RanBP2 showed prolonged mitosis or mitotic arrest, which eventually triggered mitotic cell death. Cell Chem Biol. Author manuscript; available in PMC 2017 May 08.
Wong and D’Angelo
Page 3
Author Manuscript
These findings are in agreement with the previous studies in HeLa cells (Hashizume et al., 2013). Vecchione et al. (2016) also discovered that BRAF-like CC cell lines are defective in kinetochore microtubule outgrowth and that Nup358/RanBP2 depletion further potentiates this abnormality, leading to mitotic cell death (Figure 1C). This discovery allowed them to propose that BRAF-like CC cells depend on Nup358/RanBP2 expression to tolerate the mitotic defects in microtubule nucleation from kinetochores.
Author Manuscript
The specific defect of BRAF-like cells in microtubule formation revealed a potential susceptibility of such tumors to microtubule disrupting agents. To investigate this hypothesis, Vecchione et al. (2016) tested the effect of vinorelbine, a chemotherapy medication that is mainly used for the treatment of breast and non-small cell lung cancers, on CC cell survival. Strikingly, they found that BRAF-like CC cells were 10-to 10,000-fold more sensitive to vinorelbine than non-BRAF-like cells. Using xenograft models, the authors showed that the growth of tumors derived from BRAF-like cells, but not from non-BRAFlike cells, was also inhibited by the microtubule-depolymerizing drug. Moreover, they identified that BRAF-like cells implanted into liver responded positively to vinorelbine treatment, suggesting that metastatic tumors derived from cells with the BRAF-like signature could potentially be treated with mitotic drugs. Taking all these data into consideration, the authors proposed that BRAF(V600E) could be used to predict the tumor response to DM4, a cytotoxic agent that shares a common mechanism of action to vinblastine. Using PDX models, they demonstrated that 44% of DM4 PDX responders, but none of the non-responders, carried the BRAF(V600E) mutation, supporting the authors’ hypothesis that targeting microtubule dynamics could represent a specific therapy for the treatment of BRAF-like tumors.
Author Manuscript
This work by Vecchione et al. (2016) is exciting not only because it provides evidence on how CC defend themselves from mitotic cell death, but also because it exposes a potential therapeutic pathway for the treatment of a significant percentage of CRCs with anti-mitotic drugs already approved by the FDA. As proposed by the authors, a clinical trial to assess the utility of vinorelbine in BRAF-like colon cancer is likely to follow in the near future. Finally, Nup358/RanBP2 is only one of at least ten Nups that relocate to centrosomes, spindles, and/or kinetochores during mitosis (Ibarra and Hetzer, 2015). Understanding the mitotic functions of specific Nups and dissecting their contribution to pathogenesis will likely uncover additional targets for the treatment of NPC-related diseases.
References Author Manuscript
Carethers JM, Jung BH. Gastroenterology. 2015; 149:1177–1190.e3. [PubMed: 26216840] Dawlaty MM, Malureanu L, Jeganathan KB, Kao E, Sustmann C, Tahk S, Shuai K, Grosschedl R, van Deursen JM. Cell. 2008; 133:103–115. [PubMed: 18394993] Hashizume C, Kobayashi A, Wong RW. Cell Death Dis. 2013; 4:e854. [PubMed: 24113188] Ibarra A, Hetzer MW. Genes Dev. 2015; 29:337–349. [PubMed: 25691464] Joseph J, Liu ST, Jablonski SA, Yen TJ, Dasso M. Curr Biol. 2004; 14:611–617. [PubMed: 15062103] Mariotto AB, Yabroff KR, Shao Y, Feuer EJ, Brown ML. J Natl Cancer Inst. 2011; 103:117–128. [PubMed: 21228314]
Cell Chem Biol. Author manuscript; available in PMC 2017 May 08.
Wong and D’Angelo
Page 4
Author Manuscript
Nofrini, V., Di Giacomo, D., Mecucci, C. Eur J Hum Genet. 2016. http://dx.doi.org/10.1038/ejhg. 2016.25 Popovici V, Budinska E, Tejpar S, Weinrich S, Estrella H, Hodgson G, Van Cutsem E, Xie T, Bosman FT, Roth AD, Delorenzi M. J Clin Oncol. 2012; 30:1288–1295. [PubMed: 22393095] Raices M, D’Angelo MA. Nat Rev Mol Cell Biol. 2012; 13:687–699. [PubMed: 23090414] Salina D, Enarson P, Rattner JB, Burke B. J Cell Biol. 2003; 162:991–1001. [PubMed: 12963708] Vecchione L, Gambino V, Raaijmakers J, Schlicker A, Fumagalli A, Russo M, Villanueva A, Beerling E, Bartolini A, Mollevi DG, et al. Cell. 2016; 165:317–330. [PubMed: 27058664]
Author Manuscript Author Manuscript Author Manuscript Cell Chem Biol. Author manuscript; available in PMC 2017 May 08.
Wong and D’Angelo
Page 5
Author Manuscript Author Manuscript Figure 1. From Nucleoporins to Colon Cancer, Via Mitosis
Author Manuscript
(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.
Author Manuscript Cell Chem Biol. Author manuscript; available in PMC 2017 May 08.
