Isoxazole derivatives of 6-fluoro-N-(6-methoxybenzo[d]thiazol-2-yl)benzo[d]thiazol-2-amine and N-(pyrimidin-2-yl)benzo[d]thiazol-2-amine: regulation of cell cycle and apoptosis by p53 activation via mitochondrial-dependent pathways

MedChemComm ◽  
2014 ◽  
Vol 5 (11) ◽  
pp. 1744-1750 ◽  
Author(s):  
Ravindra M. Kumbhare ◽  
Tulshiram L. Dadmal ◽  
T. Anjana Devi ◽  
Dinesh Kumar ◽  
Umesh B. Kosurkar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
P53 Activation ◽  
Regulation Of Cell Cycle ◽  
Derivatives Of ◽  
Isoxazole Derivatives

The compounds depicted were shown to induce DNA damage and activate p53, which in turn activates Bax and decreases Bcl2 levels. This resulted in apoptosis in Colo205 cells.

scholarly journals The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Eutteum Jeong ◽  
Owen A Brady ◽  
José A Martina ◽  
Mehdi Pirooznia ◽  
Ilker Tunc ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Transcription Factors ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
Cell Cycle Checkpoints ◽  
Dependent Manner ◽  
Double Knockout ◽  
Protein Levels ◽  
Regulation Of Cell Cycle

The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.

scholarly journals ADAR1 Transcriptome editing promotes breast cancer progression through the regulation of cell cycle and DNA damage response

2020 ◽  
Vol 1867 (8) ◽  
pp. 118716 ◽  
Author(s):  
Eduardo A. Sagredo ◽  
Alfredo I. Sagredo ◽  
Alejandro Blanco ◽  
Pamela Rojas De Santiago ◽  
Solange Rivas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Cancer Progression ◽  
Breast Cancer Progression ◽  
Damage Response ◽  
Regulation Of Cell Cycle

scholarly journals RB, p130 and p107 differentially repress G1/S and G2/M genes after p53 activation

2019 ◽  
Vol 47 (21) ◽  
pp. 11197-11208 ◽  
Author(s):  
Amy E Schade ◽  
Martin Fischer ◽  
James A DeCaprio
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Human Fibroblasts ◽  
Cell Cycle Gene ◽  
Cycle Progression ◽  
Cell Cycle Genes ◽  
P53 Activation ◽  
S Genes

Abstract Cell cycle gene expression occurs in two waves. The G1/S genes encode factors required for DNA synthesis and the G2/M genes contribute to mitosis. The Retinoblastoma protein (RB) and DREAM complex (DP, RB-like, E2F4 and MuvB) cooperate to repress all cell cycle genes during G1 and inhibit entry into the cell cycle. DNA damage activates p53 leading to increased levels of p21 and inhibition of cell cycle progression. Whether the G1/S and G2/M genes are differentially repressed by RB and the RB-like proteins p130 and p107 in response to DNA damage is not known. We performed gene expression profiling of primary human fibroblasts upon DNA damage and assessed the effects on G1/S and G2/M genes. Upon p53 activation, p130 and RB cooperated to repress the G1/S genes. In addition, in the absence of RB and p130, p107 contributed to repression of G1/S genes. In contrast, G2/M genes were repressed by p130 and p107 after p53 activation. Furthermore, repression of G2/M genes by p107 and p130 led to reduced entry into mitosis. Our data demonstrates specific roles for RB, p130-DREAM, and p107-DREAM in p53 and p21 mediated repression of cell cycle genes.

scholarly journals Identification of Primary Transcriptional Regulation of Cell Cycle-Regulated Genes upon DNA Damage

Cell Cycle ◽  
2007 ◽  
Vol 6 (8) ◽  
pp. 972-981 ◽  
Author(s):  
Tong Zhou ◽  
Jeff Chou ◽  
Thomas E. Mullen ◽  
Rani Elkon ◽  
Yingchun Zhou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Transcriptional Regulation ◽  
Regulation Of Cell Cycle

scholarly journals Rescue of DNA damage in cells after constricted migration reveals bimodal mechano-regulation of cell cycle

2018 ◽  
Author(s):  
Yuntao Xia ◽  
Charlotte R Pfeifer ◽  
Kuangzheng Zhu ◽  
Jerome Irianto ◽  
Dazhen Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genomic Variation ◽  
Chromatin Binding ◽  
Cell Cycle Delay ◽  
Repair Factor ◽  
Regulation Of Cell Cycle ◽  
Break Formation ◽  
Damage Marker ◽  
Partial Effects

Migration through constrictions can clearly rupture nuclei and mis-localize nuclear proteins but damage to DNA remains uncertain as does any effect on cell cycle. Here, myosin-II inhibition rescues rupture and partially rescues the DNA damage marker γH2AX, but an apparent delay in cell cycle is unaffected. Co-overexpression of multiple DNA repair factors and antioxidant inhibition of break formation also have partial effects, independent of rupture. Complete rescue of both DNA damage and cell cycle delay by myosin inhibition plus antioxidant reveals a bimodal dependence of cell cycle on DNA damage. Migration through custom-etched pores yields the same bimodal, with ~4-um pores causing intermediate levels of damage and cell cycle delay. Micronuclei (generated in faulty division) of the smallest diameter appear similar to ruptured nuclei, with high DNA damage and entry of chromatin-binding cGAS (cyclic-GMP-AMP-synthase) from cytoplasm but low repair factor levels. Increased genomic variation after constricted migration is quantified in expanding clones and is consistent with (mis)repair of excess DNA damage and subsequent proliferation.

scholarly journals Cytokinesis failure in RhoA-deficient mouse erythroblasts involves actomyosin and midbody dysregulation and triggers p53 activation

Blood ◽  
2015 ◽  
Vol 126 (12) ◽  
pp. 1473-1482 ◽  
Author(s):  
Diamantis G. Konstantinidis ◽  
Katie M. Giger ◽  
Mary Risinger ◽  
Suvarnamala Pushkaran ◽  
Ping Zhou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Deficient Mouse ◽  
Cycle Arrest ◽  
Rhoa Gtpase ◽  
Key Points ◽  
Damage Response ◽  
P53 Activation

Key Points RhoA GTPase activates pMRLC and localizes to the site of midbody formation to regulate erythroblast cytokinesis. Cytokinesis failure in erythroblasts caused by RhoA deficiency triggers p53-mediated DNA-damage response, cell-cycle arrest, and apoptosis.

scholarly journals Pin1 inhibits PP2A-mediated Rb dephosphorylation in regulation of cell cycle and S-phase DNA damage

2015 ◽  
Vol 6 (2) ◽  
pp. e1640-e1640 ◽  
Author(s):  
Y Tong ◽  
H Ying ◽  
R Liu ◽  
L Li ◽  
J Bergholz ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
S Phase ◽  
Regulation Of Cell Cycle

scholarly journals Potential Antitumor Effects of 6-Gingerol in p53-Dependent Mitochondrial Apoptosis and Inhibition of Tumor Sphere Formation in Breast Cancer Cells

2021 ◽  
Vol 22 (9) ◽  
pp. 4660
Author(s):  
Nipin Sp ◽  
Dong Young Kang ◽  
Jin-Moo Lee ◽  
Se Won Bae ◽  
Kyoung-Jin Jang
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Dna Damage ◽  
Side Effects ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Mitochondrial Apoptosis ◽  
Cycle Arrest ◽  
P53 Activation

Hormone-specific anticancer drugs for breast cancer treatment can cause serious side effects. Thus, treatment with natural compounds has been considered a better approach as this minimizes side effects and has multiple targets. 6-Gingerol is an active polyphenol in ginger with various modalities, including anticancer activity, although its mechanism of action remains unknown. Increases in the level of reactive oxygen species (ROS) can lead to DNA damage and the induction of DNA damage response (DDR) mechanism, leading to cell cycle arrest apoptosis and tumorsphere suppression. Epidermal growth factor receptor (EGFR) promotes tumor growth by stimulating signaling of downstream targets that in turn activates tumor protein 53 (p53) to promote apoptosis. Here we assessed the effect of 6-gingerol treatment on MDA-MB-231 and MCF-7 breast cancer cell lines. 6-Gingerol induced cellular and mitochondrial ROS that elevated DDR through ataxia-telangiectasia mutated and p53 activation. 6-Gingerol also induced G0/G1 cell cycle arrest and mitochondrial apoptosis by mediating the BAX/BCL-2 ratio and release of cytochrome c. It also exhibited a suppression ability of tumorsphere formation in breast cancer cells. EGFR/Src/STAT3 signaling was also determined to be responsible for p53 activation and that 6-gingerol induced p53-dependent intrinsic apoptosis in breast cancer cells. Therefore, 6-gingerol may be used as a candidate drug against hormone-dependent breast cancer cells.

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