Spatiotemporal regulation of the anaphase-promoting complex in mitosis

Sivakumar, Sushama; Gorbsky, Gary J.

doi:10.1038/nrm3934

Cited by 239 publications

(275 citation statements)

References 199 publications

(309 reference statements)

Supporting

Mentioning

271

Contrasting

Unclassified

Order By: Relevance

“…6B). APC/C is a positive regulator of mitosis and functions as an E3 ubiquitin ligase to mark cell cyclerelated proteins for proteasomal degradation (22). Loss of APC/C results in cell cycle arrest at metaphase and severe aberrations of the mitotic spindle (23).…”

Section: Kpnb1 Positively Regulates Members Of the Anaphase-promotingmentioning

confidence: 99%

In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer

Kodama

Newberg

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Epithelial ovarian cancer (EOC) is a deadly cancer, and its prognosis has not been changed significantly during several decades. To seek new therapeutic targets for EOC, we performed an in vivo dropout screen in human tumor xenografts using a pooled shRNA library targeting thousands of druggable genes. Then, in follow-up studies, we performed a second screen using a genome-wide CRISPR/Cas9 library. These screens identified 10 high-confidence drug targets that included well-known oncogenes such as ERBB2 and RAF1, and novel oncogenes, notably KPNB1, which we investigated further. Genetic and pharmacological inhibition showed that KPNB1 exerts its antitumor effects through multiphase cell cycle arrest and apoptosis induction. Mechanistically, proteomic studies revealed that KPNB1 acts as a master regulator of cell cycle-related proteins, including p21, p27, and APC/ C. Clinically, EOC patients with higher expression levels of KPNB1 showed earlier recurrence and worse prognosis than those with lower expression levels of KPNB1. Interestingly, ivermectin, a Food and Drug Administration-approved antiparasitic drug, showed KPNB1-dependent antitumor effects on EOC, serving as an alternative therapeutic toward EOC patients through drug repositioning. Last, we found that the combination of ivermectin and paclitaxel produces a stronger antitumor effect on EOC both in vitro and in vivo than either drug alone. Our studies have thus identified a combinatorial therapy for EOC, in addition to a plethora of potential drug targets.ovarian cancer | KPNB1 | loss-of-function screen | CRISPR/Cas | RNAi

show abstract

Section: Kpnb1 Positively Regulates Members Of the Anaphase-promotingmentioning

confidence: 99%

In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer

Kodama

Newberg

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…This bipolar kinetochore-microtubule attachment enables all sister chromatids to align at the metaphase plate. The anaphase-promoting complex or cyclosome (APC/C), along with its activator cell division cycle 20 (Cdc20), indirectly activates the protease separase through triggering the ubiquitination and degradation of the separase inhibitors, securin and cyclin B1 (3)(4)(5). Active separase then cleaves cohesin, leading to chromosome segregation (6,7).…”

mentioning

confidence: 99%

Structure of an intermediate conformer of the spindle checkpoint protein Mad2

Hara

Özkan

Sun

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The spindle checkpoint senses unattached kinetochores during prometaphase and inhibits the anaphase-promoting complex or cyclosome (APC/C), thus ensuring accurate chromosome segregation. The checkpoint protein mitotic arrest deficient 2 (Mad2) is an unusual protein with multiple folded states. Mad2 adopts the closed conformation (C-Mad2) in a Mad1–Mad2 core complex. In mitosis, kinetochore-bound Mad1–C-Mad2 recruits latent, open Mad2 (O-Mad2) from the cytosol and converts it to an intermediate conformer (I-Mad2), which can then bind and inhibit the APC/C activator cell division cycle 20 (Cdc20) as C-Mad2. Here, we report the crystal structure and NMR analysis of I-Mad2 bound to C-Mad2. Although I-Mad2 retains the O-Mad2 fold in crystal and in solution, its core structural elements undergo discernible rigid-body movements and more closely resemble C-Mad2. Residues exhibiting methyl chemical shift changes in I-Mad2 form a contiguous, interior network that connects its C-Mad2–binding site to the conformationally malleable C-terminal region. Mutations of residues at the I-Mad2–C-Mad2 interface hinder I-Mad2 formation and impede the structural transition of Mad2. Our study provides insight into the conformational activation of Mad2 and establishes the basis of allosteric communication between two distal sites in Mad2.

show abstract

“…During spindle checkpoint signaling, the mitotic checkpoint complex (a complex of Bub3, Mad2, and Mad3) prevents APC/C Cdc20 from ubiquitinating its substrates, however, APC/ C Cdc20 is still active to auto-ubiquitinate Cdc20. 3 An in vitro study showed that during checkpoint activation, Bub3 promotes the binding of Cdc20 and APC/C for its auto-ubiquitination. 1 We propose a model in which kinetochore localized Bub3 facilitates the binding of Cdc20 and the APC/C in metaphase.…”

mentioning

confidence: 99%

“…For the onset of anaphase, the APC/C binds its co-activator Cdc20 and targets substrates for ubiquitination and proteasomal degradation. 3 One substrate, securin, binds and inhibits separase, a protease that cleaves cohesin. The degradation of securin releases separase, promoting sister chromatid separation and anaphase onset.…”

mentioning

confidence: 99%