Role of poly(ADP-ribose) polymerase in cell-cycle checkpoint mechanisms following γ-irradiation

Biochimie ◽  
1995 ◽  
Vol 77 (6) ◽  
pp. 462-465 ◽  
Author(s):  
M. Masutani ◽  
T. Nozaki ◽  
K. Wakabayashi ◽  
T. Sugimura
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Checkpoint ◽  
Γ Irradiation ◽  
Cycle Checkpoint

scholarly journals Abnormal Micronuclear Telomeres Lead to an Unusual Cell Cycle Checkpoint and Defects in Tetrahymena Oral Morphogenesis

2008 ◽  
Vol 7 (10) ◽  
pp. 1712-1723 ◽  
Author(s):  
Karen E. Kirk ◽  
Christina Christ ◽  
Jennifer M. McGuire ◽  
Arun G. Paul ◽  
Mithaq Vahedi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mitotic Spindle ◽  
Tetrahymena Thermophila ◽  
Germ Line ◽  
Cell Cycle Checkpoint ◽  
Dna Damage Checkpoint ◽  
Telomeric Dna ◽  
Spindle Apparatus ◽  
Cycle Checkpoint

ABSTRACT Telomere mutants have been well studied with respect to telomerase and the role of telomere binding proteins, but they have not been used to explore how a downstream morphogenic event is related to the mutated telomeric DNA. We report that alterations at the telomeres can have profound consequences on organellar morphogenesis. Specifically, a telomerase RNA mutation termed ter1-43AA results in the loss of germ line micronuclear telomeres in the binucleate protozoan Tetrahymena thermophila. These cells also display a micronuclear mitotic arrest, characterized by an extreme delay in anaphase with an elongated, condensed chromatin and a mitotic spindle apparatus. This anaphase defect suggests telomere fusions and consequently a spindle rather than a DNA damage checkpoint. Most surprisingly, these mutants exhibit unique, dramatic defects in the formation of the cell's oral apparatus. We suggest that micronuclear telomere loss leads to a “dynamic pause” in the program of cortical development, which may reveal an unusual cell cycle checkpoint.

Cell cycle checkpoint defects in gastrointestinal malignancies.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 680-680
Author(s):  
Ramya Thota ◽  
Mark Andrew Lewis ◽  
Lincoln Nadauld ◽  
Derrick S. Haslem ◽  
Terence Duane Rhodes ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Checkpoint ◽  
Targeted Agents ◽  
Gastrointestinal Malignancies ◽  
Cyclin Dependent Kinases ◽  
Cycle Checkpoint ◽  
Cell Cycle Pathway ◽  
Cycle Regulation ◽  
Uncontrolled Cell Proliferation

680 Background: Cyclin Dependent Kinases (CDKs) play a significant role in cell cycle regulation. Aberrations involving the cell cycle pathway genes can lead to uncontrolled cell proliferation and genomic instability. These could potentially be targeted with CDK4/6 inhibitors. The frequency and type of these alterations in GI tumors is largely unknown. Methods: We analyzed the frequency of abnormalities in cell cycle genes in patients with diverse GI malignancies (colorectal, liver, pancreas, gastroesophageal, anal, appendix) that underwent next generation sequencing from January 2013 to August 2017. Results: Aberrations in the cell cycle pathway were identified in 33 of 299 (11%) of cancers. The frequency of aberrations was as follows: CDKN2A/B in 10 (30.3%), CCND1 in 7 patients (pts) (21.2%), CCND2 in 2 pts (6%), CEBPA in 2 pts (6%), CDK6 in 2 pts (6%), CDK8 in 2 pts (6%) and CDK2 in 1 (3%). Alteration involving multiple genes of cell cycle noted in 7 patients (21.2%) with combination of CCND1 and CDKN2A being most common combination. The cell cycle checkpoint defects were most frequently seen in 9 pts with colon (27%), 8 pts with hepatobiliary (27%), 8 pts with pancreatic (24%), 7 pts with esophageal (21%), and less commonly in small bowel (6%) and GIST (6%). Conclusions: The alterations in the cell cycle pathway are most common in certain GI tumors mainly colon, pancreatic, hepatobiliary and esophageal tumors. Future clinical trials exploring the potential role of targeted agents such as CDK4/6 inhibitors alone or in combination with other targeted agents such as MEK inhibitors requires further exploration in these tumors.

scholarly journals A Previously Unknown Unique Challenge for Inhibitors of SYK ATP-Binding Site: Role of SYK as A Cell Cycle Checkpoint Regulator

EBioMedicine ◽  
2014 ◽  
Vol 1 (1) ◽  
pp. 16-28 ◽  
Author(s):  
Fatih M. Uckun ◽  
Hong Ma ◽  
Zahide Ozer ◽  
Patricia Goodman ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Binding Site ◽  
Cell Cycle Checkpoint ◽  
Atp Binding ◽  
Unique Challenge ◽  
Atp Binding Site ◽  
Cycle Checkpoint ◽  
A Cell

scholarly journals Role of the N-terminal Forkhead-associated Domain in the Cell Cycle Checkpoint Function of the Rad53 Kinase

2001 ◽  
Vol 276 (17) ◽  
pp. 14019-14026 ◽  
Author(s):  
Brietta L. Pike ◽  
Andrew Hammet ◽  
Jörg Heierhorst
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Checkpoint ◽  
Cycle Checkpoint ◽  
Rad53 Kinase

scholarly journals 14-3-3σ Positively Regulates p53 and Suppresses Tumor Growth

2003 ◽  
Vol 23 (20) ◽  
pp. 7096-7107 ◽  
Author(s):  
Heng-Yin Yang ◽  
Yu-Ye Wen ◽  
Chih-Hsin Chen ◽  
Guillermina Lozano ◽  
Mong-Hong Lee
Keyword(s):  
Cell Cycle ◽  
Nuclear Export ◽  
Protein A ◽  
Mammary Epithelium ◽  
Cell Cycle Checkpoint ◽  
Negative Regulator ◽  
Specific Marker ◽  
Checkpoint Control ◽  
Cycle Checkpoint

ABSTRACT The 14-3-3σ (sigma) protein, a negative regulator of the cell cycle, is a human mammary epithelium-specific marker that is downregulated in transformed mammary carcinoma cells. It has also been identified as a p53-inducible gene product involved in cell cycle checkpoint control after DNA damage. Although 14-3-3σ is linked to p53-regulated cell cycle checkpoint control, detailed mechanisms of how cell cycle regulation occurs remain unclear. Decreased expression of 14-3-3σ was recently reported in several types of carcinomas, further suggesting that the negative regulatory role of 14-3-3σ in the cell cycle is compromised during tumorigenesis. However, this possible tumor-suppressive role of 14-3-3σ has not yet been characterized. Here, we studied the link between 14-3-3σ activities and p53 regulation. We found that 14-3-3σ interacted with p53 in response to the DNA-damaging agent adriamycin. Importantly, 14-3-3σ expression led to stabilized expression of p53. In studying the molecular mechanism of this increased stabilization of p53, we found that 14-3-3σ antagonized the biological functions of Mdm2 by blocking Mdm2-mediated p53 ubiquitination and nuclear export. In addition, we found that 14-3-3σ facilitated the oligomerization of p53 and enhanced p53's transcriptional activity. As a target gene of p53, 14-3-3σ appears to have a positive feedback effect on p53 activity. Significantly, we also showed that overexpression of 14-3-3σ inhibited oncogene-activated tumorigenicity in a tetracycline-regulated 14-3-3σ system. These results defined an important p53 regulatory loop and suggested that 14-3-3σ expression can be considered for therapeutic intervention in cancers.

814 SMAD4 AS A POTENTIAL GATEKEEPER FOR GENOMIC INSTABILITY AND MTOR-MEDIATED TUMORIGENESIS IN ESOPHAGEAL ADENOCARCINOMA

2021 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Julia Milne ◽  
Jovana Gotovac ◽  
Kenji Fujihara ◽  
Kaylene Simpson ◽  
Cuong Duong ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Genomic Instability ◽  
Genomic Stability ◽  
Cell Cycle Checkpoint ◽  
Synthetic Lethal ◽  
Cycle Checkpoint ◽  
Mtor Signalling ◽  
Novel Therapeutic

Abstract   Extensive genomic analysis of patient samples has identified genes whose mutation or loss map malignant progression from Barrett’s metaplasia, through low- (CDKN2A) and high-grade dysplasia (TP53), to invasive adenocarcinoma (SMAD4). Interestingly, loss of SMAD4 has been found to occur exclusively in the invasive disease stage, but the reason for this is unknown. This work aimed to characterise the role of SMAD4 in esophageal adenocarcinoma (EAC) tumorigenesis and identify novel therapeutic targets for SMAD4-deficient EAC. Methods We developed a novel in vivo tumorigenesis model that demonstrates progression of dysplastic Barrett’s esophagus (BE) to invasive EAC upon knockout of SMAD4. We conducted parallel genome-wide CRISPR-Cas9 knockout screens, both in vitro and in vivo, on a background of either wildtype-SMAD4 or SMAD4-knockout dysplastic BE cells to identify co-operative drivers of tumorigenesis in vivo, as well as synthetic lethal interactions to identify potential therapeutic targets in SMAD4-deficient EAC. Functional validation of hits was performed using cell-based assays and drugs targeting candidate molecular targets. Results We identified a synthetic lethal relationship between SMAD4-deficiency and cell cycle checkpoint inhibition, suggesting a role for SMAD4 in maintaining genomic stability and a potential novel therapeutic avenue for SMAD4-deficient EAC. A concurrent in vivo CRISPR-Cas9 tumorigenesis screen produced tumors 4-fold faster than loss of SMAD4 alone and identified regulators of mTOR signalling and SMAD4 as co-operative drivers of tumorigenesis in EAC. Interestingly, these tumorigenic cells exhibited an inherent dependency on specific translation mechanisms downstream of mTOR. Meanwhile, wildtype-SMAD4 BE cells failed to thrive in vivo with mTOR modifications alone, indicating a true co-operative effect at play with SMAD4 loss. Conclusion This study uncovered a potential gatekeeping role of SMAD4 in maintaining genomic stability and inhibiting mTOR-mediated EAC tumorigenesis. In sum, loss of SMAD4 was found to increase genomic instability, thereby rendering EAC cells sensitive to cell cycle checkpoint impediment, whilst simultaneously co-operating with modulated mTOR signalling to promote tumorigenesis in EAC xenograft models.

scholarly journals Role of c-Jun N-terminal kinase 1 (JNK1) in cell cycle checkpoint activated by the protease inhibitor N-acetyl-leucinyl-leucinyl-norleucinal

Oncogene ◽  
1999 ◽  
Vol 18 (50) ◽  
pp. 6974-6980 ◽  
Author(s):  
Wen-Wei Tchou ◽  
Ting-An Yie ◽  
Tse-Hua Tan ◽  
William N Rom ◽  
Kam-Meng Tchou-Wong
Keyword(s):  
Cell Cycle ◽  
Protease Inhibitor ◽  
Cell Cycle Checkpoint ◽  
Cycle Checkpoint
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