Insights into APC/C: from cellular function to diseases and therapeutics

Zhou, Zhuan; He, Meiling; Shah, Anil A.; Wan, Yong

doi:10.1186/s13008-016-0021-6

Cited by 104 publications

(124 citation statements)

References 172 publications

(212 reference statements)

Supporting

Mentioning

115

Contrasting

Order By: Relevance

“…The cyclin-CDK complexes themselves are regulated by cyclindependent kinase inhibitors (CKIs) including the INK4s: p16 INK4A /CDKN2A, p15 INK4B /CDKN2B, p18 INK4C /CDKN2C, and p19 INK4D /CDKN2D; and the CDK-interacting protein/kinase inhibitory proteins (CIP/KIPs): p21 CIP1/WAF1 /CDKN1A, p27 KIP1 /CDKN1B, and p57 KIP2 /CDKN1C. Additionally, E3 ubiquitin ligases are essential for regulating expression of various mitotic proteins to control cell cycle transitions, including the Skp1-Cul1-F-box-protein (SCF) complex and anaphase promoting complex/cyclosome (APC/C) [10][11][12].…”

Section: The Cell Cyclementioning

confidence: 99%

Targeting the cell cycle in breast cancer: towards the next phase

et al. 2018

View full text Add to dashboard Cite

Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Consequently, therapeutic targeting of the cell cycle has long been viewed as a promising anti-cancer strategy. Until recently, attempts to target the cell cycle for cancer therapy using selective inhibitors have proven unsuccessful due to intolerable toxicities and a lack of target specificity. However, improvements in our understanding of malignant cell-specific vulnerabilities has revealed a therapeutic window for preferential targeting of the cell cycle in cancer cells, and has led to the development of agents now in the clinic. In this review, we discuss the latest generation of cell cycle targeting anti-cancer agents for breast cancer, including approved CDK4/6 inhibitors, and investigational TTK and PLK4 inhibitors that are currently in clinical trials. In recognition of the emerging population of ER+ breast cancers with acquired resistance to CDK4/6 inhibitors we suggest new therapeutic avenues to treat these patients. We also offer our perspective on the direction of future research to address the problem of drug resistance, and discuss the mechanistic insights required for the successful implementation of these strategies.

show abstract

Section: The Cell Cyclementioning

confidence: 99%

Targeting the cell cycle in breast cancer: towards the next phase

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Hi-C spatial contacts obtained from human glutamatergic neurons shows trans-interactions between the CAMK2A gene located on chromosome 5 with the genes GRIN1 and ANAPC2 located on chromosome 9. The ANAPC2 protein is part of a complex that controls the formation of synaptic vesicle clustering at the active zone to the presynaptic membrane in postmitotic neurons, and this complex also degrades NEUROD2 as a primary component of pre-synaptic differentiation during neuronal differentiation (72). Figure 7G shows spatial contacts in neurons between the DRD2 gene and the RHOA gene, which encodes a signaling protein that regulates the cytoskeleton during synaptic transmission in neurons (73).…”

Section: Figure 7dmentioning

confidence: 99%

Ketamine’s pharmacogenomic network in human brain contains sub-networks associated with glutamate neurotransmission and with neuroplasticity

Higgins

Handelman

Allyn-Feurer

et al. 2020

Preprint

View full text Add to dashboard Cite

The pharmacogenomic network responsible for the rapid antidepressant action of ketamine and concomitant adverse events in patients has been poorly defined. Integrative, multiscale biological data analytics helps explain ketamine's action. Using a validated computational pipeline, candidate ketamine-response genes and regulatory RNAs from published literature, binding affinity studies, and single nucleotide polymorphisms (SNPs) from genomewide association studies (GWAS), we identified 108 SNPs associated with 110 genes and regulatory RNAs. All of these SNPs are classified as enhancers, and additional chromatin interaction mapping in human neural cell lines and tissue shows enhancer-promoter interactions involving other network members. Pathway analysis and gene set optimization identified three composite sub-networks within the broader ketamine pharmacogenomic network. Expression patterns of ketamine network genes within the postmortem human brain are concordant with ketamine neurocircuitry based on the results of 24 published functional neuroimaging studies. The ketamine pharmacogenomic network is enriched in forebrain regions known to be rapidly activated by ketamine, including cingulate cortex and frontal cortex, and is significantly regulated by ketamine (p=6.26E-33; Fisher's exact test). The ketamine pharmacogenomic network can be partitioned into distinct enhancer sub-networks associated with: (1) glutamate neurotransmission, chromatin remodeling, smoking behavior, schizophrenia, pain, nausea, vomiting, and post-operative delirium; (2) neuroplasticity, depression, and alcohol consumption; and (3) pharmacokinetics. The component sub-networks explain the diverse action mechanisms of ketamine and its analogs.These results may be useful for optimizing pharmacotherapy in patients diagnosed with depression, pain or related stress disorders. GRIA4 (12), and many other known (8,13) and unknown pharmacodynamic targets within human brain. Ketamine and its metabolites strongly induce the expression of the CYP2B6 gene in human brain, which encodes a drug metabolizing enzyme that contributes to first-and second-pass metabolism of the drug and its metabolites (14). Recent genomewide association studies (GWAS) in humans demonstrate association of ketamine response and adverse events with enhancers of genes and long non-coding RNAs (lncRNAs) related to the roundabout guidance receptor 2 (ROBO2) gene, whose product binds members of the slit guidance ligand family (SLIT1, SLIT2) that are involved in dendrite guidance and synaptic plasticity (15,16). Like phencyclidine, a structurally related compound, ketamine induces acute dissociation, with both drugs exhibiting species-specific differences in response. In sum, the central nervous system (CNS) pathway(s) responsible for the rapid antidepressant effects of ketamine and its enantiomers in patients diagnosed with treatment-resistant depression (TRD) remain poorly defined, including emergence of on-and off-target effects and individual differences in response and adverse eve...

show abstract

“…To differentiate cells in anaphase/telophase from those in earlier stages of mitosis, MBs targeting CDC20 mRNAs were designed to identify mitotic events where the onset of anaphase was likely to occur. CDC20 acts as a key activator promoting metaphase to anaphase transition by converging on the SAC, 26,38,39 and we hypothesized that truly proliferative (as opposed to polyploid and binucleated) CMs could be identified based on expression of mRNA encoding markers of late mitosis (CDC20 and SPG20). To accomplish this, we first optimized MB-MPG delivery by evaluating the cell viability, MB background due to endogenous nuclease degradation, and the delivery efficiency by using a positive control MB lacking its quencher ( Fig.…”

Section: Mb-mpg Delivery and Selection Of Optimal Mbs For Isolating Hmentioning

confidence: 99%

“…The cell-division cycle protein 20 (CDC20) is required to activate the anaphase promoting complex initiating chromatid separation and entrance into anaphase, leading to Securin and Cyclin B degradation and eventually mitotic exit. [23][24][25][26] Therefore we hypothesized that the level of CDC20 mRNA in live cells would be a candidate marker to indicate cell cycle status of cells in late mitosis. Likewise, the Microtubule Interacting and Trafficking molecule domain-associated gene, SPG20, is associated with the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery and cytokinesis.…”

Section: Introductionmentioning

confidence: 99%

Isolation of cardiomyocytes undergoing mitosis with complete cytokinesis

Milliron

Weiland

Kort

et al. 2019

Preprint

View full text Add to dashboard Cite

Rationale-Adult human cardiomyocytes (CMs) do not complete cytokinesis despite passing through the S-phase of the cell cycle. As a result polyploidization and multinucleation occur. In order to get a deeper understanding of the mechanisms surrounding division of CMs there is a crucial need for a technique to isolate CMs that complete cell division/cytokinesis.Objective-Markers of cell cycle progression based on DNA content cannot distinguish between mitotic CMs that fail to complete cytokinesis from those cells that undergo true cell division. With the use of molecular beacons (MB) targeting specific mRNAs we aimed to identify truly proliferative CMs derived from hiPSCs.Methods and Results-Fluorescence activated cell-sorting combined with molecular beacons was performed to sort CM populations enriched for mitotic cells. Expressions of cell-cycle specific genes were confirmed by means of RT-qPCR, single-cell RNA sequencing (scRNA-seq). We further characterized the sorted groups by proliferation assays and time-lapse microscopy which confirmed the proliferative advantage of MB-positive cell populations relative to MB-negative and G2/M populations. Gene expression analysis revealed that the MB-positive CM subpopulation exhibited patterns consistent with the biological processes of nuclear division, chromosome segregation, and transition from M to G1 phase. The use of dual-MBs targeting CDC20 and SPG20 mRNAs (CDC20 + SPG20 + ) enabled the enrichment of cytokinetic events. Interestingly, cells that did not complete cytokinesis and remained binucleated were found to be CDC20 -SPG20 + while polyploid CMs that replicated DNA but failed to complete karyokinesis were found to be CDC20 -SPG20 -.Conclusions-This study demonstrates a novel alternative to existing DNA content-based approaches for sorting CMs with true mitotic potential that can be used to study in detail the unique dynamics of CM nuclei during mitosis. Together with high-throughput scRNA-seq, our technique for sorting live CMs undergoing cytokinesis would provide a basis for future studies to uncover mechanisms underlying the development and regeneration of heart tissue.

show abstract

Insights into APC/C: from cellular function to diseases and therapeutics

Cited by 104 publications

References 172 publications

Targeting the cell cycle in breast cancer: towards the next phase

Targeting the cell cycle in breast cancer: towards the next phase

Ketamine’s pharmacogenomic network in human brain contains sub-networks associated with glutamate neurotransmission and with neuroplasticity

Isolation of cardiomyocytes undergoing mitosis with complete cytokinesis

Contact Info

Product

Resources

About