Ionizing radiation, but not ultraviolet radiation, induces mitotic catastrophe in mouse epidermal keratinocytes with aberrant cell cycle checkpoints

2018 ◽  
Vol 27 (7) ◽  
pp. 791-794 ◽  
Author(s):  
Ming Wang ◽  
QingXiang Gao ◽  
Xu Teng ◽  
MeiPing Pan ◽  
TianMiao Lin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ionizing Radiation ◽  
Ultraviolet Radiation ◽  
Cell Cycle Checkpoints ◽  
Mitotic Catastrophe ◽  
Epidermal Keratinocytes ◽  
Aberrant Cell ◽  
Mouse Epidermal Keratinocytes

scholarly journals Specific Role of Chk1 Phosphorylations in Cell Survival and Checkpoint Activation

2007 ◽  
Vol 27 (7) ◽  
pp. 2572-2581 ◽  
Author(s):  
Hiroyuki Niida ◽  
Yuko Katsuno ◽  
Birendranath Banerjee ◽  
M. Prakash Hande ◽  
Makoto Nakanishi
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Protein Kinase ◽  
Cell Survival ◽  
Cell Cycle Checkpoints ◽  
Mitotic Catastrophe ◽  
Wild Type ◽  
Checkpoint Activation ◽  
Multifunctional Protein

ABSTRACT Chk1 is a multifunctional protein kinase that plays essential roles in cell survival and cell cycle checkpoints. Chk1 is phosphorylated at multiple sites by several protein kinases, but the precise effects of these phosphorylations are largely unknown. Using a knockout-knockin system, we examined the abilities of Chk1 mutants to reverse the defects of Chk1-null cells. Wild-type Chk1 could rescue all the defects of Chk1-null cells. Like endogenous Chk1, wild-type Chk1 localized in both the cytoplasm and the nucleus, and its centrosomal association was enhanced by DNA damage. The mutation at S345 resulted in mitotic catastrophe, impaired checkpoints, and loss of the ability to localize in the cytoplasm, but the mutant retained the ability to be released from chromatin upon encountering genotoxic stressors. In contrast, the mutation at S317 resulted in impaired checkpoints and loss of chromatin release upon encountering genotoxic stressors, but its mutant retained the abilities to prevent mitotic catastrophes and to localize in the cytoplasm, suggesting the distinct effects of these phosphorylations. The forced immobilization of S317A/S345A in centrosomes resulted in the prevention of apoptosis in the presence or absence of DNA damage. Thus, two-step phosphorylation of Chk1 at S317 and S345 appeared to be required for proper localization of Chk1 to centrosomes.

scholarly journals Cholesterol protects glioblastoma cells against premature mitosis

2019 ◽  
Vol 21 (Supplement_4) ◽  
pp. iv7-iv7
Author(s):  
Natividad Gomez-roman ◽  
Mark Jackson ◽  
Anthony J Chalmers
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Primary Tumour ◽  
Specific Inhibitor ◽  
Cell Cycle Checkpoints ◽  
Mitotic Catastrophe ◽  
Anti Tumour Activity ◽  
Dismal Prognosis ◽  
Pathway Gene ◽  
Tumour Activity

Abstract Glioblastoma is the most common malignant primary tumour with a dismal prognosis. So far, no inhibitors targeting frequently altered pathways in GBM have improved patient survival. Premature entry to mitosis by small molecules that promote cancer cells to bypass the cell-cycle checkpoints have shown potent anti-tumour activity in vitro in a variety of cancers including GBM. We have reproduced these cytotoxic effects in our patient-derived GBM cell lines with the small molecule ME-344 and the Wee1-specific inhibitor AZ1775 both by by clonogenic survival and cell viability assays (EC50 values ranging from 0.003–0.02 μM and 0.2–0.4 μM, respectively). ME-344 and AZ1775 triggered profound morphological and cell cycle effects including mitotic induction, arrest and mitotic catastrophe. Bioinformatic analysis of global mRNA expression of our GBM cell lines stratified by ME-344 sensitivity showed a correlation between high ABCA1 and low cholesterol pathway gene expression with high sensitivity, and vice-versa. Cholesterol is a main component of membranes and is critical for cell growth and mitosis progression. GBM cells rely on cholesterol for survival. Due to the unique metabolic environment of the brain where a nearly unlimited supply of cholesterol is provided by astrocytes, targeting cellular activities regulated by cholesterol might lose their anti-tumour activity. Here we report that cholesterol confers cytoprotection to AZ1775 and ME344 in all GBM cell lines tested. These results suggest that cholesterol can override premature mitotic anti-tumour activity, indicating that mitotic induction and cholesterol inhibition might be a better therapeutic strategy for GBM than either treatment alone.

scholarly journals Synthetic Lethal Targeting of Mitotic Checkpoints in HPV-Negative Head and Neck Cancer

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 306 ◽  
Author(s):  
Alexander Y. Deneka ◽  
Margret B. Einarson ◽  
John Bennett ◽  
Anna S. Nikonova ◽  
Mohamed Elmekawy ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Head And Neck ◽  
Single Agent ◽  
Cell Cycle Checkpoints ◽  
Mitotic Catastrophe ◽  
Synthetic Lethal ◽  
The Us ◽  
M Phase ◽  
Dual Inhibition

Head and neck squamous cell carcinomas (HNSCC) affect more than 800,000 people annually worldwide, causing over 15,000 deaths in the US. Among HNSCC cancers, human papillomavirus (HPV)-negative HNSCC has the worst outcome, motivating efforts to improve therapy for this disease. The most common mutational events in HPV-negative HNSCC are inactivation of the tumor suppressors TP53 (>85%) and CDKN2A (>57%), which significantly impairs G1/S checkpoints, causing reliance on other cell cycle checkpoints to repair ongoing replication damage. We evaluated a panel of cell cycle-targeting clinical agents in a group of HNSCC cell lines to identify a subset of drugs with single-agent activity in reducing cell viability. Subsequent analyses demonstrated potent combination activity between the CHK1/2 inhibitor LY2606268 (prexasertib), which eliminates a G2 checkpoint, and the WEE1 inhibitor AZD1775 (adavosertib), which promotes M-phase entry, in induction of DNA damage, mitotic catastrophe, and apoptosis, and reduction of anchorage independent growth and clonogenic capacity. These phenotypes were accompanied by more significantly reduced activation of CHK1 and its paralog CHK2, and enhanced CDK1 activation, eliminating breaks on the mitotic entry of cells with DNA damage. These data suggest the potential value of dual inhibition of CHK1 and WEE1 in tumors with compromised G1/S checkpoints.

scholarly journals DNA damage checkpoint activation impairs chromatin homeostasis and promotes mitotic catastrophe during aging

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Matthew M Crane ◽  
Adam E Russell ◽  
Brent J Schafer ◽  
Ben W Blue ◽  
Riley Whalen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genome Instability ◽  
Cell Cycle Checkpoints ◽  
Mitotic Catastrophe ◽  
Dna Damage Checkpoint ◽  
Age Related ◽  
Altered Cell ◽  
Histone Transcription ◽  
Cell Cycle Dynamics

Genome instability is a hallmark of aging and contributes to age-related disorders such as cancer and Alzheimer’s disease. The accumulation of DNA damage during aging has been linked to altered cell cycle dynamics and the failure of cell cycle checkpoints. Here, we use single cell imaging to study the consequences of increased genomic instability during aging in budding yeast and identify striking age-associated genome missegregation events. This breakdown in mitotic fidelity results from the age-related activation of the DNA damage checkpoint and the resulting degradation of histone proteins. Disrupting the ability of cells to degrade histones in response to DNA damage increases replicative lifespan and reduces genomic missegregations. We present several lines of evidence supporting a model of antagonistic pleiotropy in the DNA damage response where histone degradation, and limited histone transcription are beneficial to respond rapidly to damage but reduce lifespan and genomic stability in the long term.

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