scholarly journals Gcn5p Plays an Important Role in Centromere Kinetochore Function in Budding Yeast

2007 ◽  
Vol 28 (3) ◽  
pp. 988-996 ◽  
Author(s):  
Stefano Vernarecci ◽  
Prisca Ornaghi ◽  
AnaCristina Bâgu ◽  
Enrico Cundari ◽  
Paola Ballario ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Critical Role ◽  
Chromosome Loss ◽  
Cycle Progression ◽  
Kinetochore Assembly ◽  
Spindle Elongation ◽  
And Function ◽  
Insight Into ◽  
Kinetochore Function

ABSTRACT We report that the histone acetyltransferase Gcn5p is involved in cell cycle progression, whereas its absence induces several mitotic defects, including inefficient nuclear division, chromosome loss, delayed G2 progression, and spindle elongation. The fidelity of chromosome segregation is finely regulated by the close interplay between the centromere and the kinetochore, a protein complex hierarchically assembled in the centromeric DNA region, while disruption of GCN5 in mutants of inner components results in sick phenotype. These synthetic interactions involving the ADA complex lay the genetic basis for the critical role of Gcn5p in kinetochore assembly and function. We found that Gcn5p is, in fact, physically linked to the centromere, where it affects the structure of the variant centromeric nucleosome. Our findings offer a key insight into a Gcn5p-dependent epigenetic regulation at centromere/kinetochore in mitosis.

scholarly journals A methylation-phosphorylation switch determines Plk1 kinase activity and function in DNA damage repair

2019 ◽  
Vol 5 (3) ◽  
pp. eaau7566 ◽  
Author(s):  
Weizhe Li ◽  
Hong-Yan Wang ◽  
Xiaolu Zhao ◽  
Hongguo Duan ◽  
Binghua Cheng ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Critical Role ◽  
Dna Damage Repair ◽  
Cycle Progression ◽  
Sister Chromatids ◽  
Damage Repair ◽  
And Function

Polo-like kinase 1 (Plk1) is a crucial regulator of cell cycle progression; but the mechanism of regulation of Plk1 activity is not well understood. We present evidence that Plk1 activity is controlled by a balanced methylation and phosphorylation switch. The methyltransferase G9a monomethylates Plk1 at Lys209, which antagonizes phosphorylation of T210 to inhibit Plk1 activity. We found that the methyl-deficient Plk1 mutant K209A affects DNA replication, whereas the methyl-mimetic Plk1 mutant K209M prolongs metaphase-to-anaphase duration through the inability of sister chromatids separation. We detected accumulation of Plk1 K209me1 when cells were challenged with DNA damage stresses. Ablation of K209me1 delays the timely removal of RPA2 and RAD51 from DNA damage sites, indicating the critical role of K209me1 in guiding the machinery of DNA damage repair. Thus, our study highlights the importance of a methylation-phosphorylation switch of Plk1 in determining its kinase activity and functioning in DNA damage repair.

Pentose Phosphate Pathway in Disease and Therapy

2014 ◽  
Vol 995 ◽  
pp. 1-27 ◽  
Author(s):  
Mahbuba Rahman ◽  
M. Rubayet Hasan
Keyword(s):  
Metabolic Pathways ◽  
Cell Cycle Progression ◽  
Metabolic Diseases ◽  
Pentose Phosphate ◽  
Cycle Progression ◽  
Novel Drugs ◽  
Abnormal Cells ◽  
Living Organisms ◽  
And Function

Pentose phosphate (PP) pathway, which is ubiquitously present in all living organisms, is one of the major metabolic pathways associated with glucose metabolism. The most important functions of this pathway includes the generation of reducing equivalents in the form of NADPH for reductive biosynthesis, and production of ribose sugars for the biosynthesis of nucleotides, amino acids, and other macromolecules required by all living cells. Under normal conditions of growth, PP pathway is important for cell cycle progression, myelin formation, and the maintenance of the structure and function of brain, liver, cortex and other organs. Under diseased conditions, such as in cases of many metabolic, neurological or malignant diseases, pathological mechanisms augment due to defects in the PP pathway genes. Adoption of alternative metabolic pathways by cells that are metabolically abnormal, or malignant cells that are resistant to chemotherapeutic drugs often plays important roles in disease progression and severity. Accordingly, the PP pathway has been suggested to play critical roles in protecting cancer or abnormal cells by providing reduced environment, to protect cells from oxidative damage and generating structural components for nucleic acids biosynthesis. Novel drugs that targets one or more components of the PP pathway could potentially serve to overcome challenges associated with currently available therapeutic options for many metabolic and non-metabolic diseases. However, careful designing of drugs is critical that takes into the accounts of cell’s broader genomic, proteomic and metabolic contexts under consideration, in order to avoid undesirable side-effects. In this review, we discuss the role of PP pathway under normal and abnormal physiological conditions and the potential of the PP pathway as a target for new drug development to treat metabolic and non-metabolic diseases.

scholarly journals A Critical Role of TET1/2 Proteins in Cell-Cycle Progression of Trophoblast Stem Cells

2018 ◽  
Vol 10 (4) ◽  
pp. 1355-1368 ◽  
Author(s):  
Stephanie Chrysanthou ◽  
Claire E. Senner ◽  
Laura Woods ◽  
Elena Fineberg ◽  
Hanneke Okkenhaug ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Cycle Progression ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem

The critical role of cyclin D2 in cell cycle progression and tumorigenicity of glioblastoma stem cells

Oncogene ◽  
2012 ◽  
Vol 32 (33) ◽  
pp. 3840-3845 ◽  
Author(s):  
R Koyama-Nasu ◽  
Y Nasu-Nishimura ◽  
T Todo ◽  
Y Ino ◽  
N Saito ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Cyclin D2 ◽  
Cycle Progression ◽  
Glioblastoma Stem Cells

scholarly journals Critical role of SMG7 in activation of the ATR-CHK1 axis in response to genotoxic stress

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kathleen Ho ◽  
Hongwei Luo ◽  
Wei Zhu ◽  
Yi Tang
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Genotoxic Stress ◽  
Dna Damage Checkpoint ◽  
Cycle Progression ◽  
Essential Step

AbstractCHK1 is a crucial DNA damage checkpoint kinase and its activation, which requires ATR and RAD17, leads to inhibition of DNA replication and cell cycle progression. Recently, we reported that SMG7 stabilizes and activates p53 to induce G1 arrest upon DNA damage; here we show that SMG7 plays a critical role in the activation of the ATR-CHK1 axis. Following genotoxic stress, SMG7-null cells exhibit deficient ATR signaling, indicated by the attenuated phosphorylation of CHK1 and RPA32, and importantly, unhindered DNA replication and fork progression. Through its 14-3-3 domain, SMG7 interacts directly with the Ser635-phosphorylated RAD17 and promotes chromatin retention of the 9-1-1 complex by the RAD17-RFC, an essential step to CHK1 activation. Furthermore, through maintenance of CHK1 activity, SMG7 controls G2-M transition and facilitates orderly cell cycle progression during recovery from replication stress. Taken together, our data reveals SMG7 as an indispensable signaling component in the ATR-CHK1 pathway during genotoxic stress response.

scholarly journals The Sex-Related Interplay between TME and Cancer: On the Critical Role of Estrogen, MicroRNAs and Autophagy

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3287
Author(s):  
Paola Matarrese ◽  
Gianfranco Mattia ◽  
Maria Teresa Pagano ◽  
Giada Pontecorvi ◽  
Elena Ortona ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Response To Therapy ◽  
Protective Mechanism ◽  
Epigenetic Factors ◽  
Cycle Progression ◽  
Gender Based

The interplay between cancer cells and the tumor microenvironment (TME) has a fundamental role in tumor progression and response to therapy. The plethora of components constituting the TME, such as stroma, fibroblasts, endothelial and immune cells, as well as macromolecules, e.g., hormones and cytokines, and epigenetic factors, such as microRNAs, can modulate the survival or death of cancer cells. Actually, the TME can stimulate the genetically regulated programs that the cell puts in place under stress: apoptosis or, of interest here, autophagy. However, the implication of autophagy in tumor growth appears still undefined. Autophagy mainly represents a cyto-protective mechanism that allows cell survival but, in certain circumstances, also leads to the blocking of cell cycle progression, possibly leading to cell death. Since significant sex/gender differences in the incidence, progression and response to cancer therapy have been widely described in the literature, in this review, we analyzed the roles played by key components of the TME, e.g., estrogen and microRNAs, on autophagy regulation from a sex/gender-based perspective. We focused our attention on four paradigmatic and different forms of cancers—colon cancer, melanoma, lymphoma, and lung cancer—concluding that sex-specific differences may exert a significant impact on TME/cancer interaction and, thus, tumor growth.

scholarly journals The Role of Protein SUMOylation in Human Hepatocellular Carcinoma: A Potential Target of New Drug Discovery and Development

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5700
Author(s):  
Hongchao Yuan ◽  
Yuanjun Lu ◽  
Yau-Tuen Chan ◽  
Cheng Zhang ◽  
Ning Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Tumour Microenvironment ◽  
Vital Role ◽  
Hepatic Tissue ◽  
Post Translational Modification ◽  
Cycle Progression ◽  
Potential Target

Small ubiquitin-like modifier (SUMO) is a highly conserved post-translational modification protein, mainly found in eukaryotes. They are widely expressed in different tissues, including the liver. As an essential post-translational modification, SUMOylation is involved in many necessary regulations in cells. It plays a vital role in DNA repair, transcription regulation, protein stability and cell cycle progression. Increasing shreds of evidence show that SUMOylation is closely related to Hepatocellular carcinoma (HCC). The high expression of SUMOs in the inflammatory hepatic tissue may lead to the carcinogenesis of HCC. At the same time, SUMOs will upregulate the proliferation and survival of HCC, migration, invasion and metastasis of HCC, tumour microenvironment as well as drug resistance. This study reviewed the role of SUMOylation in liver cancer. In addition, it also discussed natural compounds that modulate SUMO and target SUMO drugs in clinical trials. Considering the critical role of SUMO protein in the occurrence of HCC, the drug regulation of SUMOylation may become a potential target for treatment, prognostic monitoring and adjuvant chemotherapy of HCC.

scholarly journals Hepatitis B virus X protein stimulates cell growth by downregulating p16 levels via PA28γ-mediated proteasomal degradation

2020 ◽  
Vol 101 (9) ◽  
pp. 963-971
Author(s):  
Sungkyung Cha ◽  
Kyung Lib Jang
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Proteasomal Degradation ◽  
X Protein ◽  
Cycle Progression ◽  
B Virus

Proteasomal activator 28 gamma (PA28γ), an essential constituent of the 20S proteasome responsible for ubiquitin-independent degradation of target proteins, is frequently overexpressed in hepatocellular carcinoma. Recently, we have reported that hepatitis B virus (HBV) X protein (HBx) activates PA28γ expression in human hepatocytes via upregulation of p53 levels; however, its role in HBV tumorigenesis remains unknown. Here, we found that HBx-activated PA28γ downregulates p16 levels via ubiquitin-independent proteasomal degradation. As a result, HBx activated the Rb-E2F pathway and stimulated G1/S cell cycle progression, resulting in an increase in cell proliferation. The potential of HBx to induce these effects was reproduced in a 1.2-mer HBV replicon and in in vitro HBV infection systems and was almost completely abolished by either PA28γ knockdown or p16 overexpression, demonstrating the critical role of the PA28γ-mediated p16 degradation in HBV tumorigenesis.

scholarly journals Overlapping kinetochore targets of CK2 and Aurora B kinases in mitotic regulation

2011 ◽  
Vol 22 (15) ◽  
pp. 2680-2689 ◽  
Author(s):  
Yutian Peng ◽  
Catherine C. L. Wong ◽  
Yuko Nakajima ◽  
Randall G. Tyers ◽  
Ali S. Sarkeshik ◽  
...  
Keyword(s):  
Protein Kinase Ck2 ◽  
Cell Cycle Progression ◽  
Spindle Assembly Checkpoint ◽  
Aurora B ◽  
Cycle Progression ◽  
Spindle Microtubules ◽  
Spindle Elongation ◽  
Mitotic Regulation ◽  
Kinase Ck2 ◽  
Kinetochore Function

Protein kinase CK2 is one of the most conserved kinases in eukaryotic cells and plays essential roles in diverse processes. While we know that CK2 plays a role(s) in cell division, our understanding of how CK2 regulates cell cycle progression is limited. In this study, we revealed a regulatory role for CK2 in kinetochore function. The kinetochore is a multi-protein complex that assembles on the centromere of a chromosome and functions to attach chromosomes to spindle microtubules. To faithfully segregate chromosomes and maintain genomic integrity, the kinetochore is tightly regulated by multiple mechanisms, including phosphorylation by Aurora B kinase. We found that a loss of CK2 kinase activity inhibits anaphase spindle elongation and results in chromosome missegregation. Moreover, a lack of CK2 activates the spindle assembly checkpoint. We demonstrate that CK2 associates with Mif2, the Saccharomyces cerevisiae homologue of human CENP-C, which serves as an important link between the inner and outer kinetochore. Furthermore, we show Mif2 and the inner kinetochore protein Ndc10 are phosphorylated by CK2, and this phosphorylation plays antagonistic and synergistic roles with Aurora B phosphorylation of these targets, respectively.

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