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 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 The J Domain of Tpr2 Regulates Its Interaction with the Proapoptotic and Cell-Cycle Checkpoint Protein, Rad9

2001 ◽  
Vol 287 (4) ◽  
pp. 932-940 ◽  
Author(s):  
Shuang-Lin Xiang ◽  
Tomoyasu Kumano ◽  
Shu-ichi Iwasaki ◽  
Xiangao Sun ◽  
Kastuji Yoshioka ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Protein ◽  
Cycle Checkpoint ◽  
J Domain

scholarly journals The Maize Homologue of the Cell Cycle Checkpoint Protein MAD2 Reveals Kinetochore Substructure and Contrasting Mitotic and Meiotic Localization Patterns

1999 ◽  
Vol 145 (3) ◽  
pp. 425-435 ◽  
Author(s):  
Hong-Guo Yu ◽  
Michael G. Muszynski ◽  
R. Kelly Dawe
Keyword(s):  
Cell Cycle ◽  
Spindle Assembly ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Protein ◽  
Microtubule Attachment ◽  
Checkpoint Pathway ◽  
Outer Domain ◽  
Cycle Checkpoint ◽  
Mitosis And Meiosis ◽  
Meiosis I

We have identified a maize homologue of yeast MAD2, an essential component in the spindle checkpoint pathway that ensures metaphase is complete before anaphase begins. Combined immunolocalization of MAD2 and a recently cloned maize CENPC homologue indicates that MAD2 localizes to an outer domain of the prometaphase kinetochore. MAD2 staining was primarily observed on mitotic kinetochores that lacked attached microtubules; i.e., at prometaphase or when the microtubules were depolymerized with oryzalin. In contrast, the loss of MAD2 staining in meiosis was not correlated with initial microtubule attachment but was correlated with a measure of tension: the distance between homologous or sister kinetochores (in meiosis I and II, respectively). Further, the tension-sensitive 3F3/2 phosphoepitope colocalized, and was lost concomitantly, with MAD2 staining at the meiotic kinetochore. The mechanism of spindle assembly (discussed here with respect to maize mitosis and meiosis) is likely to affect the relative contributions of attachment and tension. We support the idea that MAD2 is attachment-sensitive and that tension stabilizes microtubule attachments.

scholarly journals Cell cycle checkpoint signaling involved in histone deacetylase inhibition and radiation-induced cell death

2005 ◽  
Vol 4 (8) ◽  
pp. 1231-1238 ◽  
Author(s):  
Ragnhild V. Nome ◽  
Åse Bratland ◽  
Gunhild Harman ◽  
Øystein Fodstad ◽  
Yvonne Andersson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Histone Deacetylase ◽  
Cell Cycle Checkpoint ◽  
Histone Deacetylase Inhibition ◽  
Checkpoint Signaling ◽  
Cycle Checkpoint ◽  
Radiation Induced

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 cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein.

1996 ◽  
Vol 93 (7) ◽  
pp. 2850-2855 ◽  
Author(s):  
K. A. Cimprich ◽  
T. B. Shin ◽  
C. T. Keith ◽  
S. L. Schreiber
Keyword(s):  
Cell Cycle ◽  
Gene Mapping ◽  
Cdna Cloning ◽  
Human Cell ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Protein ◽  
Cycle Checkpoint

scholarly journals Role of the kinetochore/cell cycle checkpoint protein ZW10 in interphase cytoplasmic dynein function

2006 ◽  
Vol 172 (5) ◽  
pp. 655-662 ◽  
Author(s):  
Dileep Varma ◽  
Denis L. Dujardin ◽  
Stephanie A. Stehman ◽  
Richard B. Vallee
Keyword(s):  
Cell Cycle ◽  
Leading Edge ◽  
Cytoplasmic Dynein ◽  
Mitotic Checkpoint ◽  
Cell Cycle Checkpoint ◽  
Dominant Negative ◽  
Checkpoint Protein ◽  
Cycle Checkpoint ◽  
Mitotic Checkpoint Protein

Zeste white 10 (ZW10) is a mitotic checkpoint protein and the anchor for cytoplasmic dynein at mitotic kinetochores, though it is expressed throughout the cell cycle. We find that ZW10 localizes to pericentriolar membranous structures during interphase and cosediments with Golgi membranes. Dominant-negative ZW10, anti-ZW10 antibody, and ZW10 RNA interference (RNAi) caused Golgi dispersal. ZW10 RNAi also dispersed endosomes and lysosomes. Live imaging of Golgi, endosomal, and lysosomal markers after reduced ZW10 expression showed a specific decrease in the frequency of minus end–directed movements. Golgi membrane–associated dynein was markedly decreased, suggesting a role for ZW10 in dynein cargo binding during interphase. We also find ZW10 enriched at the leading edge of migrating fibroblasts, suggesting that ZW10 serves as a general regulator of dynein function throughout the cell cycle.

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 Mechanism for remodelling of the cell cycle checkpoint protein MAD2 by the ATPase TRIP13

Nature ◽  
2018 ◽  
Vol 559 (7713) ◽  
pp. 274-278 ◽  
Author(s):  
Claudio Alfieri ◽  
Leifu Chang ◽  
David Barford
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Protein ◽  
Cycle Checkpoint
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