Understanding the molecular basis for cardiomyocyte cell cycle regulation: new insights in cardiac regeneration after injury?

2010 ◽  
Vol 8 (8) ◽  
pp. 1043-1045 ◽  
Author(s):  
Nuria Montserrat ◽  
Chris Jopling ◽  
Juan Carlos Izpisúa Belmonte
Keyword(s):  
Cell Cycle ◽  
Molecular Basis ◽  
Cell Cycle Regulation ◽  
Cardiac Regeneration ◽  
Cycle Regulation

Novel insights into cardiac regeneration based on differential fetal and adult ovine heart transcriptomic analysis

2020 ◽  
Vol 318 (4) ◽  
pp. H994-H1007
Author(s):  
Paola Locatelli ◽  
Mariano N. Belaich ◽  
Ayelén E. López ◽  
Fernanda D. Olea ◽  
Martín Uranga Vega ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
Differentially Expressed Gene ◽  
Cardiac Regeneration ◽  
Differentially Expressed ◽  
Cell Cycle Regulators ◽  
Large Mammal ◽  
Adult Sheep ◽  
Laboratory Rodents ◽  
Cycle Regulation

The adult mammalian cardiomyocyte has a very limited capacity to reenter the cell cycle and advance into mitosis. Therefore, diseases characterized by lost contractile tissue usually evolve into myocardial remodeling and heart failure. Analyzing the cardiac transcriptome at different developmental stages in a large mammal closer to the human than laboratory rodents may serve to disclose positive and negative cardiomyocyte cell cycle regulators potentially targetable to induce cardiac regeneration in the clinical setting. Thus we aimed at characterizing the transcriptomic profiles of the early fetal, late fetal, and adult sheep heart by employing RNA-seq technique and bioinformatic analysis to detect protein-encoding genes that in some of the stages were turned off, turned on, or differentially expressed. Genes earlier proposed as positive cell cycle regulators such as cyclin A, cdk2, meis2, meis3, and PCNA showed higher expression in fetal hearts and lower in AH, as expected. In contrast, genes previously proposed as cell cycle inhibitors, such as meis1, p16, and sav1, tended to be higher in fetal than in adult hearts, suggesting that these genes are involved in cell processes other than cell cycle regulation. Additionally, we described Gene Ontology (GO) enrichment of different sets of genes. GO analysis revealed that differentially expressed gene sets were mainly associated with metabolic and cellular processes. The cell cycle-related genes fam64a, cdc20, and cdk1, and the metabolism-related genes pitx and adipoq showed strong differential expression between fetal and adult hearts, thus being potent candidates to be targeted in human cardiac regeneration strategies. NEW & NOTEWORTHY We characterized the transcriptomic profiles of the fetal and adult sheep hearts employing RNAseq technique and bioinformatic analyses to provide sets of transcripts whose variation in expression level may link them to a specific role in cell cycle regulation. It is important to remark that this study was performed in a large mammal closer to humans than laboratory rodents. In consequence, the results can be used for further translational studies in cardiac regeneration.

scholarly journals Molecular basis of outer kinetochore assembly on CENP-T

2016 ◽  
Author(s):  
Pim J. Huis in ’t Veld ◽  
Sadasivam Jeganathan ◽  
Arsen Petrovic ◽  
Juliane John ◽  
Priyanka Singh ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Cell Cycle ◽  
Molecular Basis ◽  
Cell Cycle Regulation ◽  
Cyclin B ◽  
Kinetochore Assembly ◽  
Microtubule Attachment ◽  
Centromere Proteins ◽  
Ndc80 Complex ◽  
Cycle Regulation

Stable kinetochore-microtubule attachment is essential for cell division. It requires recruitment of outer kinetochore microtubule binders by centromere proteins C and T (CENP-C and CENP-T). To study the molecular requirements of kinetochore formation, we reconstituted the binding of the MIS12 and NDC80 outer kinetochore subcomplexes to CENP-C and CENP-T. Whereas CENP-C recruits a single MIS12:NDC80 complex, we show here that CENP-T binds one MIS12:NDC80 and two NDC80 complexes upon phosphorylation by the mitotic CDK1:Cyclin B complex at three distinct CENP-T sites. Visualization of reconstituted complexes by electron microscopy supports this model. Binding of CENP-C and CENP-T to MIS12 is competitive, and therefore CENP-C and CENP-T act in parallel to recruit two MIS12 and up to four NDC80 complexes. Our observations provide a molecular explanation for the stoichiometry of kinetochore components and its cell cycle regulation, and highlight how outer kinetochore modules bridge distances of well over 100 nm.

scholarly journals Molecular basis of outer kinetochore assembly on CENP-T

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Pim J Huis in 't Veld ◽  
Sadasivam Jeganathan ◽  
Arsen Petrovic ◽  
Priyanka Singh ◽  
Juliane John ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Cell Cycle ◽  
Molecular Basis ◽  
Cell Cycle Regulation ◽  
Cyclin B ◽  
Kinetochore Assembly ◽  
Microtubule Attachment ◽  
Centromere Proteins ◽  
Ndc80 Complex ◽  
Cycle Regulation

Stable kinetochore-microtubule attachment is essential for cell division. It requires recruitment of outer kinetochore microtubule binders by centromere proteins C and T (CENP-C and CENP-T). To study the molecular requirements of kinetochore formation, we reconstituted the binding of the MIS12 and NDC80 outer kinetochore subcomplexes to CENP-C and CENP-T. Whereas CENP-C recruits a single MIS12:NDC80 complex, we show here that CENP-T binds one MIS12:NDC80 and two NDC80 complexes upon phosphorylation by the mitotic CDK1:Cyclin B complex at three distinct CENP-T sites. Visualization of reconstituted complexes by electron microscopy supports this model. Binding of CENP-C and CENP-T to MIS12 is competitive, and therefore CENP-C and CENP-T act in parallel to recruit two MIS12 and up to four NDC80 complexes. Our observations provide a molecular explanation for the stoichiometry of kinetochore components and its cell cycle regulation, and highlight how outer kinetochore modules bridge distances of well over 100 nm.

scholarly journals Genetic variants and cognitive functions in patients with brain tumors

2019 ◽  
Vol 21 (10) ◽  
pp. 1297-1309 ◽  
Author(s):  
Denise D Correa ◽  
Jaya Satagopan ◽  
Axel Martin ◽  
Erica Braun ◽  
Maria Kryza-Lacombe ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Dna Repair ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Cell Cycle Regulation ◽  
Cognitive Outcome ◽  
Cholesterol Transport ◽  
Tumor Patients ◽  
Cycle Regulation

AbstractBackgroundPatients with brain tumors treated with radiotherapy (RT) and chemotherapy (CT) often experience cognitive dysfunction. We reported that single nucleotide polymorphisms (SNPs) in the APOE, COMT, and BDNF genes may influence cognition in brain tumor patients. In this study, we assessed whether genes associated with late-onset Alzheimer’s disease (LOAD), inflammation, cholesterol transport, dopamine and myelin regulation, and DNA repair may influence cognitive outcome in this population.MethodsOne hundred and fifty brain tumor patients treated with RT ± CT or CT alone completed a neurocognitive assessment and provided a blood sample for genotyping. We genotyped genes/SNPs in these pathways: (i) LOAD risk/inflammation/cholesterol transport, (ii) dopamine regulation, (iii) myelin regulation, (iv) DNA repair, (v) blood–brain barrier disruption, (vi) cell cycle regulation, and (vii) response to oxidative stress. White matter (WM) abnormalities were rated on brain MRIs.ResultsMultivariable linear regression analysis with Bayesian shrinkage estimation of SNP effects, adjusting for relevant demographic, disease, and treatment variables, indicated strong associations (posterior association summary [PAS] ≥ 0.95) among tests of attention, executive functions, and memory and 33 SNPs in genes involved in: LOAD/inflammation/cholesterol transport (eg, PDE7A, IL-6), dopamine regulation (eg, DRD1, COMT), myelin repair (eg, TCF4), DNA repair (eg, RAD51), cell cycle regulation (eg, SESN1), and response to oxidative stress (eg, GSTP1). The SNPs were not significantly associated with WM abnormalities.ConclusionThis novel study suggests that polymorphisms in genes involved in aging and inflammation, dopamine, myelin and cell cycle regulation, and DNA repair and response to oxidative stress may be associated with cognitive outcome in patients with brain tumors.

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