scholarly journals The cell cycle state defines TACC3 as a regulator gene in glioblastoma

2020 ◽  
Author(s):  
Holly Briggs ◽  
Euan S. Polson ◽  
Bronwyn K. Irving ◽  
Alexandre Zougman ◽  
Ryan K. Mathew ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Gene Networks ◽  
Coiled Coil ◽  
Cell Lineage ◽  
Progression Free Survival ◽  
Low Grade ◽  
Loss Of Function ◽  
Feature Maps ◽  
Clinical Databases ◽  
Lineage Specificity

AbstractOverexpression and mitosis-promoting roles of Transforming acidic coiled-coil containing protein 3 (TACC3) are well-established in many cancers, including glioblastoma (GBM). However, the effector gene networks downstream of TACC3 remain poorly defined, partly due to an incomplete understanding of TACC3 cell lineage specificity and its dynamic role during the cell cycle. Here, we use a patient-derived GBM model to report that TACC3 predominantly resides in the GBM cell cytoplasm, while engaging in gene regulation temporally as defined by the cell cycle state. TACC3 loss-of-function, cell cycle stage-specific transcriptomics, and unsupervised self-organizing feature maps revealed pathways (including Hedgehog signalling) and individual genes (including HOTAIR) that exhibited anticorrelated expression phenotypes across interphase and mitosis. Furthermore, this approach identified a set of 22 TACC3-dependent transcripts in publicly-available clinical databases that predicted poor overall and progression-free survival in 162 GBM and 514 low-grade glioma patient samples. These findings uncover TACC3-dependent genes as a function of TACC3 cell cycle oscillation, which is important for TACC3-targeting strategies, and for predicting poor outcomes in brain cancer patients.

scholarly journals Mutants of the Drosophila ncd microtubule motor protein cause centrosomal and spindle pole defects in mitosis

1994 ◽  
Vol 107 (4) ◽  
pp. 859-867 ◽  
Author(s):  
S.A. Endow ◽  
R. Chandra ◽  
D.J. Komma ◽  
A.H. Yamamoto ◽  
E.D. Salmon
Keyword(s):  
Cell Cycle ◽  
Coiled Coil ◽  
Motor Protein ◽  
Spindle Pole ◽  
Opposite Polarity ◽  
Microtubule Assembly ◽  
Loss Of Function ◽  
Spindle Poles ◽  
Microtubule Motor ◽  
Microtubule Motor Protein

Nonclaret disjunctional (ncd) is a kinesin-related microtubule motor protein required for meiotic and early mitotic chromosome distribution in Drosophila. ncd translocates on microtubules with the opposite polarity to kinesin, toward microtubule minus ends, and is associated with spindles in chromosome/spindle preparations. Here we report a new mutant of ncd caused by partial deletion of the predicted coiled-coil central stalk. The mutant protein exhibits a velocity of translocation and ability to generate torque in motility assays comparable to near full-length ncd, but only partially rescues a null mutant for chromosome mis-segregation. Antibody staining experiments show that the partial loss-of-function and null mutants cause centrosomal and spindle pole defects, including centrosome splitting and loss of centrosomes from spindle poles, and localize ncd to centrosomes as well as spindles of wild-type embryos. Association of ncd with spindles and centrosomes is microtubule- and cell cycle-dependent: inhibition of microtubule assembly with colchicine abolishes ncd staining and centrosomal staining is observed in prometaphase, metaphase and anaphase, but diminishes in late anaphase/telophase. The cell cycle dependence of centrosomal staining and the defects of mutants provide clear evidence for activity of the ncd motor protein near or at the spindle poles in mitosis. The ncd motor may interact with centrosomal microtubules and spindle fibers to attach centrosomes to spindle poles, and mediate poleward translocation (flux) of kinetochore fibers, a process that may underlie poleward movement of chromosomes in mitosis. Together with previous work, our findings indicate that ncd is important in maintaining spindle poles in mitosis as well as in meiosis.

Organ-specific cell division abnormalities caused by mutation in a general cell cycle regulator inC. elegans

Development ◽  
2002 ◽  
Vol 129 (9) ◽  
pp. 2155-2165
Author(s):  
Ivana Kostić ◽  
Richard Roy
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Ectopic Expression ◽  
Cell Lineage ◽  
Intestinal Cells ◽  
Specific Cell ◽  
Cell Cycle Regulators ◽  
Loss Of Function ◽  
C Elegans ◽  
Cell Divisions

The precise control of cell division during development is pivotal for morphogenesis and the correct formation of tissues and organs. One important gene family involved in such control is the p21/p27/p57 class of negative cell cycle regulators. Loss of function of the C. elegans p27 homolog, cki-1, causes extra cell divisions in numerous tissues including the hypodermis, the vulva, and the intestine. We have sought to better understand how cell divisions are controlled upstream or in parallel to cki-1 in specific organs during C. elegans development. By taking advantage of the invariant cell lineage of C. elegans, we used an intestinal-specific GFP reporter in a screen to identify mutants that undergo cell division abnormalities in the intestinal lineage. We have isolated a mutant with twice the wild-type complement of intestinal cells, all of which arise during mid-embryogenesis. This mutant, called rr31, is a fully dominant, maternal-effect, gain-of-function mutation in the cdc-25.1 cell cycle phosphatase that sensitizes the intestinal lineage to an extra cell division. We showed that cdc-25.1 acts at the G1/S transition, as ectopic expression of CDC-25.1 caused entry into S phase in intestinal cells. In addition, we showed that the cdc-25.1(gf) requires cyclin E. The extra cell division defect was shown to be restricted to the E lineage and the E fate is necessary and sufficient to sensitize cells to this mutation.

scholarly journals RIP140 Represses Intestinal Paneth Cell Differentiation and Interplays with SOX9 Signaling in Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3192
Author(s):  
Antoine Gleizes ◽  
Mouna Triki ◽  
Sandrine Bonnet ◽  
Naomi Baccari ◽  
Gabriel Jimenez-Dominguez ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Differentiation ◽  
Paneth Cell ◽  
Wnt Signaling Pathway ◽  
Cell Lineage ◽  
Human Colon ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Sox9 Expression ◽  
Human Colon Cancer

RIP140 is a major transcriptional coregulator of gut homeostasis and tumorigenesis through the regulation of Wnt/APC signaling. Here, we investigated the effect of RIP140 on Paneth cell differentiation and its interplay with the transcription factor SOX9. Using loss of function mouse models, human colon cancer cells, and tumor microarray data sets we evaluated the role of RIP140 in SOX9 expression and activity using RT-qPCR, immunohistochemistry, luciferase reporter assays, and GST-pull down. We first evidence that RIP140 strongly represses the Paneth cell lineage in the intestinal epithelium cells by inhibiting Sox9 expression. We then demonstrate that RIP140 interacts with SOX9 and inhibits its transcriptional activity. Our results reveal that the Wnt signaling pathway exerts an opposite regulation on SOX9 and RIP140. Finally, the levels of expression of RIP140 and SOX9 exhibit a reverse response and prognosis value in human colorectal cancer biopsies. This work highlights an intimate transcriptional cross-talk between RIP140 and SOX9 in intestinal physiopathology.

scholarly journals NCOG-38. CLINICAL CHARACTERISTICS OF LOW GRADE GLIOMA PATIENTS WITH NON-CANONICAL IDH1 AND IDH2 MUTATIONS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii137-ii137
Author(s):  
Katherine Peters ◽  
Eric Lipp ◽  
Gloria Broadwater ◽  
James Herndon ◽  
Margaret Johnson ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Point Mutations ◽  
Progression Free Survival ◽  
Idh1 Mutation ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Who Grade ◽  
Targeted Mutation ◽  
Kaplan Meier ◽  
Idh1 And Idh2 Mutations

Abstract BACKGROUND Low grade gliomas (LGGs) develop in young adults and represent 10-15% of all glial tumors. While LGG patients can have longer survival than higher grade tumors, progression, transformation, and ultimately mortality occurs. Mutations in Isocitrate dehydrogenase 1/2 (IDH1/IDH2) are prevalent in LGG and are responsible for gliomagenesis. The classic IDH1 mutation is located at 132 codon and represented as p.Arg132His, but there are non-canonical IDH1 and IDH2 mutations. We sought to compare clinical characteristics of LGG patients with classic IDH1 p.Arg132His mutation to LGG patients with non-canonical IDH1 and IDH2 mutations. METHODS We queried an IRB-approved registry retrospectively from 12/2004- 9/2019. We included IDH1/IDH2 mutant LGG (WHO grade II) and known IDH1 and IDH2 targeted mutation analysis using standard PCR followed by DNA sequencing to detect point mutations in IDH1/IDH2 genes. We obtained available clinical and histopathological data. We estimated progression-free survival (PFS), time to transformation (TT), and overall survival (OS) using Kaplan-Meier methods. RESULTS We identified 267 LGG patients with median follow-up of 9.1 yrs (95%CI 8.4-9.9 yrs). Classic IDH1 p.Arg132His mutation occurred in 223 (83.9%) patients. IDH2 mutations occurred in 14 (5.2%) patients. Non-canonical IDH1 mutations were in 30 (11.2%) patients and included the following mutations: p.Arg132Cys (13), p.Arg132Gly (10), p.Arg132Ser (4), p.Arg132Leu (1), p.Arg119Gln (1), and p.Arg172Met (1). Initial presentation, OS, and TT did not differ between IDH1/IDH2 groups. PFS differed significantly between groups with improved median PFS in IDH2 mutant LGG (5.4 yrs; 95%CI 3.5-25.2) versus classic IDH1 mutant LGG (4.1 yrs; 95%CI 3.7-4.9 yrs) and non-canonical IDH1 mutant LGG (2.6 yrs; 95%CI 2.1-4.8) (log-rank p=0.019). Notably, non-canonical mutations were more common in astrocytoma (22/30; 73.3%) than other LGG histologies (p=0.018). CONCLUSIONS In this cohort, LGG patients with non-canonical mutations have a shorter time to progression than patients with classic p.Arg132His mutation and IDH2 mutations.

scholarly journals β-elemene alleviates airway stenosis via the ILK/Akt pathway modulated by MIR143HG sponging miR-1275

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Guoying Zhang ◽  
Cheng Xue ◽  
Yiming Zeng
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Cell Model ◽  
Protective Efficacy ◽  
Rabbit Model ◽  
Akt Pathway ◽  
Loss Of Function ◽  
Airway Stenosis

Abstract Background We have previously found that β-elemene could inhibit the viability of airway granulation fibroblasts and prevent airway hyperplastic stenosis. This study aimed to elucidate the underlying mechanism and protective efficacy of β-elemene in vitro and in vivo. Methods Microarray and bioinformatic analysis were used to identify altered pathways related to cell viability in a β-elemene-treated primary cell model and to construct a β-elemene-altered ceRNA network modulating the target pathway. Loss of function and gain of function approaches were performed to examine the role of the ceRNA axis in β-elemene's regulation of the target pathway and cell viability. Additionally, in a β-elemene-treated rabbit model of airway stenosis, endoscopic and histological examinations were used to evaluate its therapeutic efficacy and further verify its mechanism of action. Results The hyperactive ILK/Akt pathway and dysregulated LncRNA-MIR143HG, which acted as a miR-1275 ceRNA to modulate ILK expression, were suppressed in β-elemene-treated airway granulation fibroblasts; β-elemene suppressed the ILK/Akt pathway via the MIR143HG/miR-1275/ILK axis. Additionally, the cell cycle and apoptotic phenotypes of granulation fibroblasts were altered, consistent with ILK/Akt pathway activity. In vivo application of β-elemene attenuated airway granulation hyperplasia and alleviated scar stricture, and histological detections suggested that β-elemene's effects on the MIR143HG/miR-1275/ILK axis and ILK/Akt pathway were in line with in vitro findings. Conclusions MIR143HG and ILK may act as ceRNA to sponge miR-1275. The MIR143HG/miR-1275/ILK axis mediates β-elemene-induced cell cycle arrest and apoptosis of airway granulation fibroblasts by modulating the ILK/Akt pathway, thereby inhibiting airway granulation proliferation and ultimately alleviating airway stenosis.

scholarly journals A survival analysis of surgically treated incidental low-grade glioma patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lingcheng Zeng ◽  
Qi Mei ◽  
Hua Li ◽  
Changshu Ke ◽  
Jiasheng Yu ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Total Resection ◽  
Surgical Timing ◽  
Asymptomatic Group ◽  
Free Survival ◽  
Symptomatic Group ◽  
Significant Difference ◽  
Asymptomatic Phase

AbstractTo evaluate the surgical effect on survival in patients with incidental low-grade glioma (LGG) through comparison between asymptomatic and symptomatic patients. The medical records of surgically treated adult cerebral incidental LGG (iLGG) patients in our department between January 2008 and December 2015 were retrospectively reviewed. The survival of patients was calculated starting from the initial imaging diagnosis. Factors related to progression-free survival (PFS), overall survival (OS) and malignant progression-free survival (MPFS) were statistically analyzed. Seventy-five iLGG patients underwent surgery: 49 in the asymptomatic group, who underwent surgery in the asymptomatic period, and 26 in the symptomatic group, who underwent surgery after the tumor had grown and the patients had developed tumor-related symptoms. Significantly more tumors were initially located adjacent to the functional area in the symptomatic group than in the asymptomatic group (P < 0.05), but there was no significant difference in the total resection rate between the two groups. The incidence of postoperative complications (15.4%) and postoperative epilepsy (23.1%) was higher in the symptomatic group than in the asymptomatic group (4.1% and 10.2%, respectively). Multivariate analysis showed that surgical timing, namely, surgery performed before or after symptom occurrence, had no significant effect on PFS, OS or MPFS, while total resection significantly prolonged PFS, OS and MPFS, and the pathology of oligodendroglioma was positively correlated with PFS and OS (P < 0.05). Surgical timing for iLGGs should facilitate total resection. If total resection can be achieved, even after symptom occurrence, patients can achieve comparable survival benefits to those treated with surgery in the asymptomatic phase.

scholarly journals RTID-05. INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF VORASIDENIB (AG-881) VS PLACEBO IN PATIENTS WITH RESIDUAL/RECURRENT GRADE II GLIOMA WITH AN ISOCITRATE DEHYDROGENASE 1/2 (IDH1/2) MUTATION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii194-ii194
Author(s):  
Ingo Mellinghoff ◽  
Martin van den Bent ◽  
Jennifer Clarke ◽  
Elizabeth Maher ◽  
Katherine Peters ◽  
...  
Keyword(s):  
High Risk ◽  
Dose Escalation ◽  
Objective Response ◽  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
High Risk Population ◽  
Low Grade ◽  
Who Grade ◽  
Free Survival ◽  
Grade Ii

Abstract BACKGROUND Low-grade gliomas (LGGs; WHO grade II) are incurable and ultimately progress to high-grade gliomas. The current treatment options are surgery followed by observation (“watch and wait”) for patients with lower risk for disease progression or postoperative chemoradiotherapy (high-risk population). There are no approved targeted therapies. IDH1 and IDH2 mutations (mIDH1/2) occur in approximately 80% and 4% of LGGs, respectively, and promote tumorigenesis via neomorphic production of D-2-hydroxyglutarate. Vorasidenib, an oral, potent, reversible, brain-penetrant pan-inhibitor of mIDH1/2, was evaluated in 76 patients with glioma in two phase 1 studies (dose escalation and perioperative) and was associated with a favorable safety profile at daily doses below 100 mg. Preliminary clinical activity was observed in non-enhancing glioma patients in both studies, with an objective response rate (ORR) of 18.2% and median progression-free survival of 31.4 months in the dose escalation study. METHODS Approximately 366 patients will be randomized 1:1 to vorasidenib (50 mg QD) or matched placebo and stratified by 1p19q status (intact vs co-deleted). Key eligibility criteria: age ≥ 12 years; grade II oligodendroglioma or astrocytoma (per WHO 2016 criteria) not in need of immediate treatment and without high-risk features; centrally confirmed mIDH1/2 status; ≥ 1 surgery for glioma with most recent ≥ 1 year but ≤ 5 years before randomization, and no other anticancer therapy; Karnofsky performance status ≥ 80%; and centrally confirmed measurable, non-enhancing disease evaluable by magnetic resonance imaging. Crossover from placebo to the vorasidenib arm is permitted upon centrally confirmed radiographic progression per RANO-LGG criteria. Primary endpoint: progression-free survival assessed by independent review. Secondary endpoints: safety and tolerability, tumor growth rate assessed by volume, ORR, overall survival, and quality of life. Clinical data will be reviewed regularly by an independent data monitoring committee. The study is currently enrolling patients in the US, with additional countries planned (NCT04164901).

scholarly journals Loss-of-function of p53 isoform Δ113p53 accelerates brain aging in zebrafish

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Ting Zhao ◽  
Shengfan Ye ◽  
Zimu Tang ◽  
Liwei Guo ◽  
Zhipeng Ma ◽  
...  
Keyword(s):  
Replicative Senescence ◽  
Brain Aging ◽  
Ventricular Zone ◽  
Human Fibroblasts ◽  
Cell Lineage ◽  
Lineage Tracing ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Antioxidant Genes ◽  
Age Related

AbstractReactive oxygen species (ROS) stress has been demonstrated as potentially critical for induction and maintenance of cellular senescence, and been considered as a contributing factor in aging and in various neurological disorders including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). In response to low-level ROS stress, the expression of Δ133p53, a human p53 isoform, is upregulated to promote cell survival and protect cells from senescence by enhancing the expression of antioxidant genes. In normal conditions, the basal expression of Δ133p53 prevents human fibroblasts, T lymphocytes, and astrocytes from replicative senescence. It has been also found that brain tissues from AD and ALS patients showed decreased Δ133p53 expression. However, it is uncharacterized if Δ133p53 plays a role in brain aging. Here, we report that zebrafish Δ113p53, an ortholog of human Δ133p53, mainly expressed in some of the radial glial cells along the telencephalon ventricular zone in a full-length p53-dependent manner. EDU-labeling and cell lineage tracing showed that Δ113p53-positive cells underwent cell proliferation to contribute to the neuron renewal process. Importantly, Δ113p53M/M mutant telencephalon possessed less proliferation cells and more senescent cells compared to wild-type (WT) zebrafish telencephalon since 9-months old, which was associated with decreased antioxidant genes expression and increased level of ROS in the mutant telencephalon. More interestingly, unlike the mutant fish at 5-months old with cognition ability, Δ113p53M/M zebrafish, but not WT zebrafish, lost their learning and memory ability at 19-months old. The results demonstrate that Δ113p53 protects the brain from aging by its antioxidant function. Our finding provides evidence at the organism level to show that depletion of Δ113p53/Δ133p53 may result in long-term ROS stress, and finally lead to age-related diseases, such as AD and ALS in humans.

scholarly journals DDRE-03. IDH1-MUTANT GBM CELLS ARE HIGHLY SENSITIVE TO COMBINATION OF KDM6A/B AND HDAC INHIBITORS

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i6-i7
Author(s):  
Alişan Kayabölen ◽  
Gizem Nur Sahin ◽  
Fidan Seker ◽  
Ahmet Cingöz ◽  
Bekir Isik ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Mutant Cell ◽  
Glioma Cells ◽  
Epigenetic Therapy ◽  
Low Grade ◽  
Orthotopic Model ◽  
Cycle Arrest ◽  
Mutant Cells

Abstract Mutations in IDH1 and IDH2 genes are common in low grade gliomas and secondary GBM and are known to cause a distinct epigenetic landscape in these tumors. To interrogate the epigenetic vulnerabilities of IDH-mutant gliomas, we performed a chemical screen with inhibitors of chromatin modifiers and identified 5-azacytidine, Chaetocin, GSK-J4 and Belinostat as potent agents against primary IDH1-mutant cell lines. Testing the combinatorial efficacy of these agents, we demonstrated GSK-J4 and Belinostat combination as a very effective treatment for the IDH1-mutant glioma cells. Engineering established cell lines to ectopically express IDH1R132H, we showed that IDH1R132H cells adopted a different transcriptome with changes in stress-related pathways that were reversible with the mutant IDH1 inhibitor, GSK864. The combination of GSK-J4 and Belinostat was highly effective on IDH1R132H cells, but not on wt glioma cells or nonmalignant fibroblasts and astrocytes. The cell death induced by GSK-J4 and Belinostat combination involved the induction of cell cycle arrest and apoptosis. RNA sequencing analyses revealed activation of inflammatory and unfolded protein response pathways in IDH1-mutant cells upon treatment with GSK-J4 and Belinostat conferring increased stress to glioma cells. Specifically, GSK-J4 induced ATF4-mediated integrated stress response and Belinostat induced cell cycle arrest in primary IDH1-mutant glioma cells; which were accompanied by DDIT3/CHOP-dependent upregulation of apoptosis. Moreover, to dissect out the responsible target histone demethylase, we undertook genetic approach and demonstrated that CRISPR/Cas9 mediated ablation of both KDM6A and KDM6B genes phenocopied the effects of GSK-J4 in IDH1-mutant cells. Finally, GSK-J4 and Belinostat combination significantly decreased tumor growth and increased survival in an orthotopic model in mice. Together, these results suggest a potential combination epigenetic therapy against IDH1-mutant gliomas.

scholarly journals LGG-06. LONG-TERM OUTCOME OF NEWLY DIAGNOSED LOW GRADE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii367-iii367
Author(s):  
Nongnuch Sirachainan ◽  
Attaporn Boongerd ◽  
Samart Pakakasama ◽  
Usanarat Anurathapan ◽  
Ake Hansasuta ◽  
...  
Keyword(s):  
Surgical Management ◽  
Progression Free Survival ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Newly Diagnosed ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Common Location ◽  
Suprasellar Region

Abstract INTRODUCTION Low grade glioma (LGG) is the most common central nervous system (CNS) tumor in children accounted for 30–50%. Regarding benign characteristic of disease, surgical management remains the mainstay of treatment. However, surgical approach is limited in some conditions such as location at brainstem or infiltrative tumor. Chemotherapy and radiation treatments have been included in order to control tumor progression. The 5-years survival rate is approach 90% especially in patients who receive complete resection. However, the outcome of children with LGG in low to middle income is limited. Therefore, the aim of the study was to determine long-term outcome of children with newly diagnosed LGG. METHODS A retrospective study enrolled children aged &lt;18 years who were newly diagnosed LGG during January 2006- December 2019. Diagnosis of LGG was confirmed by histological findings of grade I and II according to WHO criteria. RESULTS A total of 40 patients, female to male ratio was 1:1.35 and mean (SD) for age was 6.7 (4.0) years. The most common location was optic chiasmatic pathway (42.5%), followed by suprasellar region (25.0%). Sixty percent of patients received at least partial tumor removal. Chemotherapy and radiation had been used in 70% and 10.0% respectively. The 10-year progression free survival was 74.1±11.4% and overall survival was 96.2±3.8%. SUMMARY: Treatment of Pediatric LGG mainly required surgical management, however, chemotherapy and radiation had been used in progressive disease. The outcome was excellent.

Sign in / Sign up

Export Citation Format

Share Document