Importin-β negatively regulates multiple aspects of mitosis including RANGAP1 recruitment to kinetochores

Roscioli, Emanuele; Francesco, Laura Di; Bolognesi, Alessio; Giubettini, Maria; Orlando, Serena; Harel, Amnon; Schininà, Maria Eugenia; Lavia, Patrizia

doi:10.1083/jcb.201109104

Cited by 49 publications

(67 citation statements)

References 59 publications

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“…Kpnb1 plays a vital role in mitosis, where it plays a role in spindle regulation and nuclear envelope and pore assembly (50). Both Kpnb1 inhibition with siRNA (48) and Kpnb1 overexpression (4,5) have been shown to result in mitotic defects and mitotic arrest, hence the induction of a mitotic block after INI-43 treatment supports INI-43 as an agent that interferes with cell-cycle progression in the G 2 -M phase where Kpnb1 has previously been reported to play a role.…”

Section: Discussionmentioning

confidence: 99%

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Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic

Watt

Chi

Stelma

et al. 2016

Molecular Cancer Therapeutics

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Karyopherin beta 1 (Kpnb1) is a nuclear transport receptor that imports cargoes into the nucleus. Recently, elevated Kpnb1 expression was found in certain cancers and Kpnb1 silencing with siRNA was shown to induce cancer cell death. This study aimed to identify novel small molecule inhibitors of Kpnb1, and determine their anticancer activity. An in silico screen identified molecules that potentially bind Kpnb1 and Inhibitor of Nuclear Import-43, INI-43

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Section: Discussionmentioning

confidence: 99%

“…This is highlighted by the fact that ectopic overexpression of Kpnb1 results in distinct mitotic defects (4,5). The right balance of Kpnb1 is thus necessary for correct cell functioning.…”

Section: Introductionmentioning

confidence: 96%

Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic

Watt

Chi

Stelma

et al. 2016

Molecular Cancer Therapeutics

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“…The binding to importin-β keeps these factors inactive (Ciciarello et al, 2007;Clarke and Zhang, 2008;Kalab and Heald, 2008), hence keeping mitotic progression on schedule by preventing the premature onset of mitotic events; importin-β acts therefore as a global negative regulator of mitosis (reviewed by Forbes et al, 2015). When overexpressed, importin-β causes an array of mitotic abnormalities (Nachury et al, 2001;Ciciarello et al, 2004;Kaláb et al, 2006), including the inhibition of RANGAP1 localisation to KTs (Roscioli et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Importin-β and CRM1 control a RANBP2 spatiotemporal switch essential for mitotic kinetochore function

Gilistro

Turris

Damizia

et al. 2017

Journal of Cell Science

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Protein conjugation with small ubiquitin-related modifier (SUMO) is a post-translational modification that modulates protein interactions and localisation. RANBP2 is a large nucleoporin endowed with SUMO E3 ligase and SUMO-stabilising activity, and is implicated in some cancer types. RANBP2 is part of a larger complex, consisting of SUMO-modified RANGAP1, the GTP-hydrolysis activating factor for the GTPase RAN. During mitosis, the RANBP2-SUMO-RANGAP1 complex localises to the mitotic spindle and to kinetochores after microtubule attachment. Here, we address the mechanisms that regulate this localisation and how they affect kinetochore functions. Using proximity ligation assays, we find that nuclear transport receptors importin-β and CRM1 play essential roles in localising the RANBP2-SUMO-RANGAP1 complex away from, or at kinetochores, respectively. Using newly generated inducible cell lines, we show that overexpression of nuclear transport receptors affects the timing of RANBP2 localisation in opposite ways. Concomitantly, kinetochore functions are also affected, including the accumulation of SUMOconjugated topoisomerase-IIα and stability of kinetochore fibres. These results delineate a novel mechanism through which nuclear transport receptors govern the functional state of kinetochores by regulating the timely deposition of RANBP2.

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“…There is therefore a functional cross-talk between proteins that regulate MT/KT interactions, and RSSU recruitment to KTs, which in turn reinforces these interactions. Interestingly, CRM1 is required for the RSSU complex recruitment to KTs while importin beta overexpression inhibits it (Roscioli et al, 2012). However, neither endogenous RANBP2, nor GFPtagged RANBP2 constructs, localize to KTs in MEFs (Hamada et al, 2011).…”

Section: -Mitotic Microtubule-kinetochore Interactionsmentioning

confidence: 99%