scholarly journals Developmental alterations in centrosome integrity contribute to the post-mitotic state of mammalian cardiomyocytes

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
David C Zebrowski ◽  
Silvia Vergarajauregui ◽  
Chi-Chung Wu ◽  
Tanja Piatkowski ◽  
Robert Becker ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Nuclear Envelope ◽  
Regenerative Therapy ◽  
Microtubule Organizing Center ◽  
Potential Explanation ◽  
Cycle Arrest ◽  
Adult Cardiomyocytes ◽  
Organizing Center ◽  
G1 Cell Cycle Arrest ◽  
Center Loss

Mammalian cardiomyocytes become post-mitotic shortly after birth. Understanding how this occurs is highly relevant to cardiac regenerative therapy. Yet, how cardiomyocytes achieve and maintain a post-mitotic state is unknown. Here, we show that cardiomyocyte centrosome integrity is lost shortly after birth. This is coupled with relocalization of various centrosome proteins to the nuclear envelope. Consequently, postnatal cardiomyocytes are unable to undergo ciliogenesis and the nuclear envelope adopts the function as cellular microtubule organizing center. Loss of centrosome integrity is associated with, and can promote, cardiomyocyte G0/G1 cell cycle arrest suggesting that centrosome disassembly is developmentally utilized to achieve the post-mitotic state in mammalian cardiomyocytes. Adult cardiomyocytes of zebrafish and newt, which are able to proliferate, maintain centrosome integrity. Collectively, our data provide a novel mechanism underlying the post-mitotic state of mammalian cardiomyocytes as well as a potential explanation for why zebrafish and newts, but not mammals, can regenerate their heart.

scholarly journals A novel ligand of the translationally controlled tumor protein (TCTP) identified by virtual drug screening for cancer differentiation therapy

2021 ◽  
Author(s):  
Nicolas Fischer ◽  
Ean-Jeong Seo ◽  
Sara Abdelfatah ◽  
Edmond Fleischer ◽  
Anette Klinger ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Virtual Screening ◽  
Small Molecules ◽  
Large Scale ◽  
Differentiation Therapy ◽  
P53 Expression ◽  
Microscale Thermophoresis ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Mcf 7

SummaryIntroduction Differentiation therapy is a promising strategy for cancer treatment. The translationally controlled tumor protein (TCTP) is an encouraging target in this context. By now, this field of research is still at its infancy, which motivated us to perform a large-scale screening for the identification of novel ligands of TCTP. We studied the binding mode and the effect of TCTP blockade on the cell cycle in different cancer cell lines. Methods Based on the ZINC-database, we performed virtual screening of 2,556,750 compounds to analyze the binding of small molecules to TCTP. The in silico results were confirmed by microscale thermophoresis. The effect of the new ligand molecules was investigated on cancer cell survival, flow cytometric cell cycle analysis and protein expression by Western blotting and co-immunoprecipitation in MOLT-4, MDA-MB-231, SK-OV-3 and MCF-7 cells. Results Large-scale virtual screening by PyRx combined with molecular docking by AutoDock4 revealed five candidate compounds. By microscale thermophoresis, ZINC10157406 (6-(4-fluorophenyl)-2-[(8-methoxy-4-methyl-2-quinazolinyl)amino]-4(3H)-pyrimidinone) was identified as TCTP ligand with a KD of 0.87 ± 0.38. ZINC10157406 revealed growth inhibitory effects and caused G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. ZINC10157406 (2 × IC50) downregulated TCTP expression by 86.70 ± 0.44% and upregulated p53 expression by 177.60 ± 12.46%. We validated ZINC10157406 binding to the p53 interaction site of TCTP and replacing p53 by co-immunoprecipitation. Discussion ZINC10157406 was identified as potent ligand of TCTP by in silico and in vitro methods. The compound bound to TCTP with a considerably higher affinity compared to artesunate as known TCTP inhibitor. We were able to demonstrate the effect of TCTP blockade at the p53 binding site, i.e. expression of TCTP decreased, whereas p53 expression increased. This effect was accompanied by a dose-dependent decrease of CDK2, CDK4, CDK, cyclin D1 and cyclin D3 causing a G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. Our findings are supposed to stimulate further research on TCTP-specific small molecules for differentiation therapy in oncology.

scholarly journals Arctigenin, a natural lignan compound, induces G0/G1 cell cycle arrest and apoptosis in human glioma cells

2016 ◽  
Vol 13 (2) ◽  
pp. 1007-1013 ◽  
Author(s):  
Aisha Maimaitili ◽  
Zunhua Shu ◽  
Xiaojiang Cheng ◽  
Kadeer Kaheerman ◽  
Alifu Sikandeer ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Glioma Cells ◽  
Human Glioma ◽  
Human Glioma Cells ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

The G1 cell cycle arrest of macrophages infected withAggregatibacter actinomycetemcomitans

Oral Diseases ◽  
2010 ◽  
Vol 16 (3) ◽  
pp. 305-309 ◽  
Author(s):  
H Kasai ◽  
K Nakashima ◽  
M Yokota ◽  
T Nishihara
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

scholarly journals p53-dependent repression of CDK4 translation in TGF-beta-induced G1 cell-cycle arrest.

1995 ◽  
Vol 9 (2) ◽  
pp. 204-217 ◽  
Author(s):  
M E Ewen ◽  
C J Oliver ◽  
H K Sluss ◽  
S J Miller ◽  
D S Peeper
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Tgf Beta ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

scholarly journals Induction of p53-Independent Apoptosis and G1 Cell Cycle Arrest by Fucoidan in HCT116 Human Colorectal Carcinoma Cells

Marine Drugs ◽  
2017 ◽  
Vol 15 (6) ◽  
pp. 154 ◽  
Author(s):  
Hye Park ◽  
Shin-Hyung Park ◽  
Jin-Woo Jeong ◽  
Dahye Yoon ◽  
Min Han ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Colorectal Carcinoma ◽  
Cell Cycle Arrest ◽  
Carcinoma Cells ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Human Colorectal Carcinoma

CEP110 and ninein are located in a specific domain of the centrosome associated with centrosome maturation

2002 ◽  
Vol 115 (9) ◽  
pp. 1825-1835 ◽  
Author(s):  
Young Y. Ou ◽  
Gary J. Mack ◽  
Meifeng Zhang ◽  
Jerome B. Rattner
Keyword(s):  
Cell Cycle ◽  
Protein Interactions ◽  
Protein Function ◽  
Similar Distribution ◽  
Microtubule Organizing Center ◽  
Specific Domain ◽  
The Reformation ◽  
Mother And Daughter ◽  
Organizing Center ◽  
Pericentriolar Material

The mammalian centrosome consists of a pair of centrioles surrounded by pericentriolar material (PCM). The architecture and composition of the centrosome, especially the PCM, changes during the cell cycle. Recently, a subset of PCM proteins have been shown to be arranged in a tubular conformation with an open and a closed end within the centrosome. The presence of such a specific configuration can be used as a landmark for mapping proteins in both a spatial and a temporal fashion. Such mapping studies can provide information about centrosome organization, protein dynamics,protein-protein interactions as well as protein function. In this study, the centrosomal proteins CEP110 and ninein were mapped in relationship to the tubular configuration. Both proteins were found to exhibit a similar distribution pattern. In the mother centrosome, they were found at both ends of the centrosome tube, including the site of centrosome duplication. However,in the daughter centrosome they were present only at the closed end. At the closed end of the mother and daughter centrosome tube, both CEP110 and ninein co-localized with the centriolar protein CEP250/c-Nap1, which confirms ninein's centriole association and places CEP110 in association with this structure. Importantly, the appearance of CEP110 and ninein at the open end of the daughter centrosome occurred during the telophase-G1 transition of the next cell cycle, concomitant with the maturation of the daughter centrosome into a mother centrosome. Microinjection of antibodies against either CEP110 or ninein into metaphase HeLa cells disrupted the reformation of the tubular conformation of proteins within the centrosome following cell division and consequently led to dispersal of centrosomal material throughout the cytosol. Further, microinjection of antibodies to either CEP110 or ninein into metaphase PtK2 cells not only disrupted the tubular configuration within the centrosome but also affected the centrosome's ability to function as a microtubule organizing center (MTOC). This MTOC function was also disrupted when the antibodies were injected into postmitotic cells. Taken together, our results indicate that: (1) a population of CEP110 and ninein is located in a specific domain within the centrosome, which corresponds to the open end of the centrosome tube and is the site of protein addition associated with maturation of a daughter centrosome into a mother centrosome; and (2) the addition of CEP110 and ninein are essential for the reformation of specific aspects of the interphase centrosome architecture following mitosis as well as being required for the centrosome to function as a MTOC.

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