scholarly journals SOG1 transcription factor promotes the onset of endoreduplication under salinity stress in Arabidopsis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kalyan Mahapatra ◽  
Sujit Roy
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Transcription Factor ◽  
Programmed Cell Death ◽  
Salinity Stress ◽  
Crucial Role ◽  
Genome Stability ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Regulators

AbstractAs like in mammalian system, the DNA damage responsive cell cycle checkpoint functions play crucial role for maintenance of genome stability in plants through repairing of damages in DNA and induction of programmed cell death or endoreduplication by extensive regulation of progression of cell cycle. ATM and ATR (ATAXIA-TELANGIECTASIA-MUTATED and -RAD3-RELATED) function as sensor kinases and play key role in the transmission of DNA damage signals to the downstream components of cell cycle regulatory network. The plant-specific NAC domain family transcription factor SOG1 (SUPPRESSOR OF GAMMA RESPONSE 1) plays crucial role in transducing signals from both ATM and ATR in presence of double strand breaks (DSBs) in the genome and found to play crucial role in the regulation of key genes involved in cell cycle progression, DNA damage repair, endoreduplication and programmed cell death. Here we report that Arabidopsis exposed to high salinity shows generation of oxidative stress induced DSBs along with the concomitant induction of endoreduplication, displaying increased cell size and DNA ploidy level without any change in chromosome number. These responses were significantly prominent in SOG1 overexpression line than wild-type Arabidopsis, while sog1 mutant lines showed much compromised induction of endoreduplication under salinity stress. We have found that both ATM-SOG1 and ATR-SOG1 pathways are involved in the salinity mediated induction of endoreduplication. SOG1was found to promote G2-M phase arrest in Arabidopsis under salinity stress by downregulating the expression of the key cell cycle regulators, including CDKB1;1, CDKB2;1, and CYCB1;1, while upregulating the expression of WEE1 kinase, CCS52A and E2Fa, which act as important regulators for induction of endoreduplication. Our results suggest that Arabidopsis undergoes endoreduplicative cycle in response to salinity induced DSBs, showcasing an adaptive response in plants under salinity stress.

scholarly journals Differentiating life and death: An inflammatory affair

2018 ◽  
Author(s):  
Dustin Lane
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Differentiation ◽  
Programmed Cell Death ◽  
Signaling Networks ◽  
Inhibitors Of Apoptosis ◽  
Life And Death ◽  
Cell Death Signaling ◽  
Cycle Dependent

Programmed cell death signaling networks are frequently activated to coordinate the process of cell differentiation, and a variety of apoptotic events can mediate the process. This can include the ligation of death receptors, the activation of downstream caspases, and the induction of chromatin fragmentation, and all of these events can occur without downstream induction of death. Importantly, regulators of programmed cell death also have established roles in mediating differentiation. This review will provide an overview of apoptosis and its regulation by Inhibitors of Apoptosis (IAPs) and Bcl-2 family members. It will then outline the cross-talk between NF-ĸB and apoptotic signaling in the regulation of apoptosis before discussing the function of these regulators in the control of cell differentiation. It will end on a discussion of how a DNA damage-directed, cell cycle-dependent differentiation program may be controlled across multiple passages through cell cycle, and will assert that the failure to properly differentiate is the underlying cause of cancer.

DNA replication and damage checkpoints and meiotic cell cycle controls in the fission and budding yeasts

2000 ◽  
Vol 349 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Hiroshi MURAKAMI ◽  
Paul NURSE
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Fission Yeast ◽  
Molecular Mechanisms ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Regulators ◽  
Meiotic Cell ◽  
Checkpoint Proteins ◽  
Dna Damage Checkpoints

The cell cycle checkpoint mechanisms ensure the order of cell cycle events to preserve genomic integrity. Among these, the DNA-replication and DNA-damage checkpoints prevent chromosome segregation when DNA replication is inhibited or DNA is damaged. Recent studies have identified an outline of the regulatory networks for both of these controls, which apparently operate in all eukaryotes. In addition, it appears that these checkpoints have two arrest points, one is just before entry into mitosis and the other is prior to chromosome separation. The former point requires the central cell-cycle regulator Cdc2 kinase, whereas the latter involves several key regulators and substrates of the ubiquitin ligase called the anaphase promoting complex. Linkages between these cell-cycle regulators and several key checkpoint proteins are beginning to emerge. Recent findings on post-translational modifications and protein-protein interactions of the checkpoint proteins provide new insights into the checkpoint responses, although the functional significance of these biochemical properties often remains unclear. We have reviewed the molecular mechanisms acting at the DNA-replication and DNA-damage checkpoints in the fission yeast Schizosaccharomyces pombe, and the modifications of these controls during the meiotic cell cycle. We have made comparisons with the controls in fission yeast and other organisms, mainly the distantly related budding yeast.

G2/M Arrest Sensitizes Chronic Myelogenous Leukemia Cells to TRAIL-Induced Apoptosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4465-4465
Author(s):  
David Devlin ◽  
Eva Szegezdi ◽  
Paavilainen Tanja ◽  
Orsolya Orosz ◽  
Michael O'Dwyer ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Cycle Progression ◽  
Cell Cycle Checkpoint ◽  
Myelogenous Leukemia ◽  
Leukemia Cells ◽  
Induced Apoptosis ◽  
Cycle Dependent ◽  
Low Sensitivity

Abstract Abstract 4465 The death ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receives great interest as it targets and kills cancerous cells, but not non-transformed cells. While it is in phase I/II clinical trials for a range of solid tumours, the generally low sensitivity of leukemia cells to TRAIL makes it a less attractive therapeutic for these cancers. We found that doxorubicin and cytarabine, agents that induce DNA damage and impair cell cycle progression, can sensitize CML cells to TRAIL with CI<1 at Fa of ED25 and ED50 (based on median-effect method using the isobologram equation). Inhibition of the cell cycle checkpoint kinases Chk1/2 with UCN-01 did not influence TRAIL-induced apoptosis nor could it abolish the sensitizing effect of doxorubicin. Interestingly, inhibition of Ataxia Telangiectasia Mutated (ATM), a key DNA damage response kinase, with KU-55933 induced a G2/M arrest and enhanced TRAIL-induced apoptosis. Inhibition of ATM alone induced 22±3.1% apoptosis and increased TRAIL-induced apoptosis from 27.2±4.7% to 68±7.2%. Cell cycle analysis revealed that while the proportion of cells in the G0/G1 and S phases slightly increased, the proportion of the cells in the G2/M phase dropped by 31.6±3.2% (p<0.05) indicating that G2/M arrested cells were more sensitive to TRAIL than cells in G0/G1 and S phases. TRAIL-induced CML cell death was also synergistically enhanced by arresting the cells in G2/M using the microtubule disrupting drugs, nocodazole or colcemide. Cells were treated with a concentration of nocodazole or colcemide that induced above 90% G2/M arrest for 16 h (0.3 mM and 0.1 mg/ml, respectively) followed by treatment with 250 ng/ml of TRAIL for 24 h. Nocodazole, colcemide and TRAIL individually induced 19±3.7% 26.3±4.4% and 27.2±4.7% cell death, while combination of nocodazole or colcemide with TRAIL resulted 89±6.8% and 93±5.9% cell death, respectively. In summary, we found that induction of DNA damage sensitizes CML cells to TRAIL and that TRAIL-sensitivity of CML cells is cell cycle-dependent. Disclosures: O'Dwyer: Novartis: Honoraria.

scholarly journals Differentiating life and death: An inflammatory affair

2018 ◽  
Author(s):  
Dustin Lane
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Differentiation ◽  
Programmed Cell Death ◽  
Signaling Networks ◽  
Inhibitors Of Apoptosis ◽  
Life And Death ◽  
Cell Death Signaling ◽  
Cycle Dependent

Programmed cell death signaling networks are frequently activated to coordinate the process of cell differentiation, and a variety of apoptotic events can mediate the process. This can include the ligation of death receptors, the activation of downstream caspases, and the induction of chromatin fragmentation, and all of these events can occur without downstream induction of death. Importantly, regulators of programmed cell death also have established roles in mediating differentiation. This review will provide an overview of apoptosis and its regulation by Inhibitors of Apoptosis (IAPs) and Bcl-2 family members. It will then outline the cross-talk between NF-ĸB and apoptotic signaling in the regulation of apoptosis before discussing the function of these regulators in the control of cell differentiation. It will end on a discussion of how a DNA damage-directed, cell cycle-dependent differentiation program may be controlled across multiple passages through cell cycle, and will assert that the failure to properly differentiate is the underlying cause of cancer.

scholarly journals Negative regulator of E2F transcription factors links cell cycle checkpoint and DNA damage repair

2018 ◽  
Vol 115 (16) ◽  
pp. E3837-E3845 ◽  
Author(s):  
Lili Wang ◽  
Hanchen Chen ◽  
Chongyang Wang ◽  
Zhenjie Hu ◽  
Shunping Yan
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Transcription Factors ◽  
Genome Stability ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Checkpoints ◽  
Negative Regulator ◽  
Cycle Checkpoint ◽  
E2f Transcription Factors

DNA damage poses a serious threat to genome integrity and greatly affects growth and development. To maintain genome stability, all organisms have evolved elaborate DNA damage response mechanisms including activation of cell cycle checkpoints and DNA repair. Here, we show that the DNA repair protein SNI1, a subunit of the evolutionally conserved SMC5/6 complex, directly links these two processes in Arabidopsis. SNI1 binds to the activation domains of E2F transcription factors, the key regulators of cell cycle progression, and represses their transcriptional activities. In turn, E2Fs activate the expression of SNI1, suggesting that E2Fs and SNI1 form a negative feedback loop. Genetically, overexpression of SNI1 suppresses the phenotypes of E2F-overexpressing plants, and loss of E2F function fully suppresses the sni1 mutant, indicating that SNI1 is necessary and sufficient to inhibit E2Fs. Altogether, our study revealed that SNI1 is a negative regulator of E2Fs and plays dual roles in DNA damage responses by linking cell cycle checkpoint and DNA repair.

scholarly journals Inhibition of WEE1 Induces Cell Death of Both Bortezomib- and Lenalidomide-Resistant Multiple Myeloma Cells: A Novel Therapeutic Approach Targeting Cell-Cycle Checkpoint Kinase

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3256-3256 ◽  
Author(s):  
Takayuki Tabayashi ◽  
Yuka Tanaka ◽  
Yasuyuki Takahashi ◽  
Yuta Kimura ◽  
Tatsuki Tomikawa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Apoptotic Cell ◽  
Cell Cycle Checkpoint ◽  
Dependent Manner ◽  
Checkpoint Kinase ◽  
Cycle Arrest ◽  
Cycle Checkpoint ◽  
Novel Therapeutic

Abstract Multiple myeloma (MM) is a hematological malignancy that derives from the proliferation of unregulated plasma cells. Dramatic improvement in the clinical outcomes of both newly diagnosed and relapsed/refractory patients with MM has been achieved using many clinical approaches, including use of high-dose chemotherapy followed by hematopoietic stem cell transplantation, and new drugs, such as proteasome inhibitors, immunomodulatory drugs, and histone deacetylase inhibitors. However, most patients eventually relapse and develop drug resistance. Moreover, the prognosis of patients with bortezomib (BTZ) and/or lenalidomide (LEN)-resistant MM (key drugs in the treatment of MM) is very poor. Therefore, novel therapeutic approaches to overcome BTZ and LEN resistance are urgently needed in clinical settings. WEE1 is a cell-cycle checkpoint kinase and a key regulator of DNA damage surveillance pathways. In response to extrinsically induced DNA damage, WEE1 catalyzes inhibitory phosphorylation of both cyclin-dependent kinase1 and 2 (CDK1 and CDK2), leading to CDK1- and CDK2-induced cell cycle arrest at the G1, S, or G2-M phases. This cell-cycle arrest, in turn, allows for the damaged DNA to be repaired before the cell undergoes DNA replication, and prevents cells harboring unrepaired damaged DNA from mitotic lethality. Furthermore, recent research has shown that knockdown of WEE1 leads to DNA double-strand breaks specifically in S-phase cells undergoing DNA replication, and that WEE1 is most active in the S-phase, suggesting that WEE1 is involved in DNA synthesis. Overexpression of WEE1 has been observed in many types of cancers, including hepatic cancer, breast cancer, glioblastoma and gastric cancer, and high expression of WEE1 has been shown to correlate with poor prognosis. In addition, research has shown that inhibition of checkpoint kinase 1 (Chk1), a critical transducer of the DNA damage response, potentiates the cytotoxicity of chemotherapy on p53-deficient MM cells, which are regarded as chemotherapy-resistant, suggesting that inhibition of cell-cycle checkpoint kinase is involved in re-sensitization of refractory MM cells to anticancer drugs. These data suggest that WEE1 might be an attractive target for novel therapeutic agents against this incurable hematological malignancy. MK-1775 is a potent and highly-selective small-molecule inhibitor of WEE1. In the present study, we investigated the role of WEE1 in MM as a potential therapeutic target using MK-1775. MTSassays showed that single agent MK-1775 inhibited the proliferation of various MM cell lines, including the intrinsically LEN-resistant cell line, RPMI-8226, in a dose- (0 to 10 mM) and time- (0 to 72 h) dependent manner. Furthermore, the growth inhibition effect is irrespective of p53 status. To examine the mechanisms behind the growth inhibition effect induced by MK-1775, assays for apoptotic cell death were performed. These assays demonstrated that MK-1775 induces both early and late apoptosis in MM cells. To investigate the molecular mechanisms of MK-1775-induced cell death in MM cells, the expression of various cell death-associated proteins and downstream molecules of WEE1 were examined. Western blotting analysis showed that MK-1775 arrested cell growth and induced apoptotic cell death in MM cells in a dose-dependent manner by inhibiting both, the expression of the target molecules of Bcl-2 and MCL1, and the cleavage of PARP and Caspase 3. Similarly, there was a substantial inhibition of CDK1 phosphorylation downstream of WEE1. Moreover, an increased expression of histone H2AX was observed following administration of MK-1775, suggesting that MK-1775 results in cytotoxicity by direct DNA damage. Next, we examined the effects of MK-1775 on BTZ-resistant MM cells. Interestingly, MK-1775 inhibited the proliferation of both BTZ-sensitive wild-type MM cells and BTZ-resistant MM cells, suggesting that BTZ resistance can be overcome by targeting WEE1. Furthermore, in combination with BTZ, MK-1775 was able to re-sensitize BTZ-resistant MM cells to BTZ. These results indicate that inhibition of WEE1 might serve as an attractive therapeutic option for patients with both BTZ-resistant and LEN-resistant MM. In conclusion, our data suggest that WEE1 might be a promising molecular target for the treatment of MM. Disclosures Tokuhira: Bristol Myers Squibb Co., Ltd: Honoraria; Pfizer Co., Ltd: Honoraria; Eizai Co., Ltd: Honoraria.

scholarly journals Dual Targeting of Cell-Cycle Checkpoint Kinase and Unfolded Protein Response As a Novel Therapeutic Approach for High-Risk Multiple Myeloma with TP53 Deletion or Mutations

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5613-5613
Author(s):  
Yuka Tanaka ◽  
Takayuki Tabayashi ◽  
Yasuyuki Takahashi ◽  
Yuta Kimura ◽  
Tatsuki Tomikawa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Research Funding ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Cell Cycle Checkpoint ◽  
Unfolded Protein ◽  
Cycle Checkpoint ◽  
Tp53 Status

Abstract Multiple myeloma (MM) is a hematological malignancy characterized by abnormal clonal proliferation of malignant plasma cells. Despite the introduction of novel agents such as proteasome inhibitors, immunomodulatory drugs, and antibodies that have significantly improved clinical outcomes of the patients of MM, most patients eventually relapse and develop drug resistance. In particular, the prognosis of patients harboring either chromosome TP53 deletion or mutations remains very poor, suggesting the prevalence of TP53 abnormalities increases with disease progression. Therefore, novel therapeutic strategies to overcome this unfavorable feature are urgently needed in clinical settings. WEE1 is a cell-cycle checkpoint kinase and a key regulator of DNA damage surveillance pathways. In response to extrinsically induced DNA damage, WEE1 kinase induces cell cycle arrest, allowing damaged DNA to be repaired before the cell undergoes DNA replication in S phase, and preventing cells harboring unrepaired, damaged DNA from mitotic lethality. Furthermore, WEE1 overexpression has been observed in many types of cancers. In addition, our previous studies revealed that monotherapy with AZD1775, a potent and highly selective inhibitor of WEE1, inhibited the proliferation of various MM cell lines irrespective of TP53 status. (Blood 2016; 128: 3256). On the other hand, one of the defining features of MM cells is the production of large amounts of protein, such as immunoglobulin, that must be processed within the endoplasmic reticulum (ER). Due to the accumulation of abundant immunoglobulin in ER, MM cells are constitutively under conditions of ER stress. The unfolded protein response (UPR)-signaling pathway is a cytoprotective mechanism against ER stress, and is therefore activated in MM cells to survive these conditions. Activation of the UPR has been observed in many types of cancers, and loss of TP53 has shown to enhance the UPR. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is one of three ER transmembrane protein kinases implicated as primary effectors of the UPR. Recent studies have suggested that PERK inhibition resulted in dose-dependent inhibition of tumor growth both in vitro and in vivo. In addition, more recent studies have proposed that PERK induces resistance to cell death elicited by chemotherapy. The combination of WEE1 and PERK inhibitors might thus offer an attractive therapeutic option against this incurable hematological malignancy. Here, we investigated the therapeutic utility of AZD1775 and GSK2606414, a highly selective inhibitor of PERK kinase, alone and in combination in various MM cells including TP53 wild-type (MM1.S) as well as TP53-deficient (KMS-11) and TP53-mutated (U266, RPMI8226, OPM-2) cell lines. AZD1775 and GSK2606414 alone induced dose-dependent cell growth inhibition in all investigated MM cells irrespective of TP53 status. Interestingly, GSK2606414 in combination with AZD1775 inhibited proliferation of all MM cells more effectively than either single agent. Assays for apoptotic cell death demonstrated that AZD1775 in combination with GSK2606414 induced significant and marked apoptotic cell death in MM cells used in this study compared to monotherapy alone. Next, western blotting analysis was performed to address the mechanisms of apoptotic cell death by the treatment of WEE1 and PERK inhibitors in MM cells. GSK2606414 inhibited PERK activation and decreased its downstream substrates (phospho-eIF2a, ATF4, and CHOP). Combination treatment with WEE1 inhibitor and various doses of PERK inhibitor significantly increased PARP and caspase 3 cleavage, CDK1 phosphorylation, and histone H2AX expression. Taken together, these data suggest that combining AZD1775 and GSK2606414 synergistically induced DNA damage and promoted premature mitotic entry, resulting in apoptotic cell death of TP53-deleted or -mutated MM cells. In conclusion, dual targeting of WEE1 and PERK might be a promising therapeutic approach for MM irrespective of TP53 status. Disclosures Tokuhira: Bristol-Myers Squibb: Speakers Bureau; AYUMI Pharmaceutical Corporation: Speakers Bureau; Mitsubishi Tanabe Pharma Corporation: Speakers Bureau; Chugai: Speakers Bureau. Kizaki:Novartis: Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Nippon Shinyaku,: Research Funding, Speakers Bureau.

scholarly journals The bacterial cell cycle checkpoint protein Obg and its role in programmed cell death

2016 ◽  
Vol 3 (6) ◽  
pp. 255-256 ◽  
Author(s):  
Liselot Dewachter ◽  
Natalie Verstraeten ◽  
Maarten Fauvart ◽  
Jan Michiels
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Bacterial Cell ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Protein ◽  
Cycle Checkpoint ◽  
Bacterial Cell Cycle

scholarly journals Hcm1 integrates signals from Cdk1 and calcineurin to control cell proliferation

2015 ◽  
Vol 26 (20) ◽  
pp. 3570-3577 ◽  
Author(s):  
Heather E. Arsenault ◽  
Jagoree Roy ◽  
Claudine E. Mapa ◽  
Martha S. Cyert ◽  
Jennifer A. Benanti
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Chromosome Segregation ◽  
Genome Stability ◽  
Control Cell ◽  
Cell Cycle Regulators ◽  
Cyclin Dependent Kinase ◽  
Expression Of Genes ◽  
Response To Stress

Cyclin-dependent kinase (Cdk1) orchestrates progression through the cell cycle by coordinating the activities of cell-cycle regulators. Although phosphatases that oppose Cdk1 are likely to be necessary to establish dynamic phosphorylation, specific phosphatases that target most Cdk1 substrates have not been identified. In budding yeast, the transcription factor Hcm1 activates expression of genes that regulate chromosome segregation and is critical for maintaining genome stability. Previously we found that Hcm1 activity and degradation are stimulated by Cdk1 phosphorylation of distinct clusters of sites. Here we show that, upon exposure to environmental stress, the phosphatase calcineurin inhibits Hcm1 by specifically removing activating phosphorylations and that this regulation is important for cells to delay proliferation when they encounter stress. Our work identifies a mechanism by which proliferative signals from Cdk1 are removed in response to stress and suggests that Hcm1 functions as a rheostat that integrates stimulatory and inhibitory signals to control cell proliferation.

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