Polyomavirus large- and small-T relieve middle-T-induced cell cycle arrest in normal fibroblasts

Papovavirus tumour antigens have been widely used to study cell growth regulation in cultured cells. We investigated the role of mouse polyomavirus T antigens, small-, middle- and large-T, in stimulating growth-arrested REF52 fibroblasts to enter the S phase. Microinjecting cells with cDNAs encoding the various T antigens showed: first, that middle-T expression blocked cell cycle stimulation by serum; second, that middle-T-arrested cells were released into the S phase upon coexpression of small-T; third, that expression of middle-T together with large-T committed resting cells to enter the cell cycle even in the absence of serum. Our data indicate that extensive cooperation among polyomavirus T antigens is essential for T antigen-mediated cell cycle stimulation in growth-arrested cells. In addition, the data suggest a new role for small-T in signalling to mitogenic pathways.

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Prolonged arrest of mammalian cells at the G1/S boundary results in permanent S phase stasis

Journal of Cell Science ◽

10.1242/jcs.115.14.2829 ◽

2002 ◽

Vol 115 (14) ◽

pp. 2829-2838

Author(s):

Franck Borel ◽

Françoise B. Lacroix ◽

Robert L. Margolis

Keyword(s):

Cell Cycle ◽

Dna Replication ◽

Mammalian Cells ◽

Cell Cycle Progression ◽

T Antigen ◽

S Phase ◽

Inhibitory Circuits ◽

Cycle Arrest ◽

Mcm Proteins

Mammalian cells in culture normally enter a state of quiescence during G1 following suppression of cell cycle progression by senescence, contact inhibition or terminal differentiation signals. We find that mammalian fibroblasts enter cell cycle stasis at the onset of S phase upon release from prolonged arrest with the inhibitors of DNA replication, hydroxyurea or aphidicolin. During arrest typical S phase markers remain present, and G0/G1 inhibitory signals such as p21WAF1 and p27 are absent. Cell cycle stasis occurs in T-antigen transformed cells, indicating that p53 and pRB inhibitory circuits are not involved. While no DNA replication is evident in arrested cells, nuclei isolated from these cells retain measurable competence for in vitro replication. MCM proteins are required to license replication origins, and are put in place in nuclei in G1 and excluded from chromatin by the end of replication to prevent rereplication of the genome. Strikingly, MCM proteins are strongly depleted from chromatin during prolonged S phase arrest,and their loss may underlie the observed cell cycle arrest. S phase stasis may thus be a `trap' in which cells otherwise competent for S phase have lost a key component required for replication and thus can neither go forward nor retreat to G1 status.

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Knockdown of MRPL42 suppresses glioma cell proliferation by inducing cell cycle arrest and apoptosis

Bioscience Reports ◽

10.1042/bsr20171456 ◽

2018 ◽

Vol 38 (2) ◽

Cited By ~ 2

Author(s):

Chunyan Hao ◽

Hubin Duan ◽

Hao Li ◽

Huan Wang ◽

Yueting Liu ◽

...

Keyword(s):

Cell Cycle ◽

Ribosomal Proteins ◽

Glioma Cells ◽

S Phase ◽

The Cancer Genome Atlas ◽

Normal Tissues ◽

Cycle Arrest ◽

Glioma Cell Proliferation ◽

Cancer Genome Atlas

Mammalian mitochondrial ribosomal proteins are functionally involved in protein synthesis in mitochondrion. Recently numerous studies have illuminated the role of mitochondrion in cancer development. However, the precise function of mitochondrial ribosomal protein L42 (MRPL42) remains unclear. Here in the present study, we identified MRPL42 as a novel oncogene in glioma. By analyzing the Cancer Genome Atlas (TCGA) database, we first found that MRPL42 was significantly up-regulated in glioma tissues compared with normal tissues. Functionally, we silenced MRPL42 in glioma cells and revealed that MRPL42 knockdown largely blunted the proliferation of U251 and A172 cells. Mechanistically, our results suggested that MRPL42 silencing resulted in increased distribution of cell cycle in G1 and G2/M phases, while the S-phase decreased. In addition, the apoptosis and caspase3/7 activity were both activated after MRPL42 knockdown. Taken together, MRPL42 is a novel oncogene in glioma and might help us develop promising targetted therapies for glioma patients.

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β-Catenin Regulation during the Cell Cycle: Implications in G2/M and Apoptosis

Molecular Biology of the Cell ◽

10.1091/mbc.e03-01-0865 ◽

2003 ◽

Vol 14 (7) ◽

pp. 2844-2860 ◽

Cited By ~ 129

Author(s):

David Olmeda ◽

Susanna Castel ◽

Senén Vilaró ◽

Amparo Cano

Keyword(s):

Cell Cycle ◽

S Phase ◽

Epidermal Keratinocytes ◽

Stable Form ◽

Multifunctional Protein ◽

Cycle Arrest ◽

M Phase ◽

Positive Modulator ◽

G2 Cell Cycle Arrest

β-catenin is a multifunctional protein involved in cell-cell adhesion and Wnt signal transduction. β-Catenin signaling has been proposed to act as inducer of cell proliferation in different tumors. However, in some developmental contexts and cell systems β-catenin also acts as a positive modulator of apoptosis. To get additional insights into the role of β-Catenin in the regulation of the cell cycle and apoptosis, we have analyzed the levels and subcellular localization of endogenous β-catenin and its relation with adenomatous polyposis coli (APC) during the cell cycle in S-phase–synchronized epithelial cells. β-Catenin levels increase in S phase, reaching maximum accumulation at late G2/M and then abruptly decreasing as the cells enter into a new G1 phase. In parallel, an increased cytoplasmic and nuclear localization of β-catenin and APC is observed during S and G2 phases. In addition, strong colocalization of APC with centrosomes, but not β-catenin, is detected in M phase. Interestingly, overexpression of a stable form of β-catenin, or inhibition of endogenous β-catenin degradation, in epidermal keratinocyte cells induces a G2 cell cycle arrest and leads to apoptosis. These results support a role for β-catenin in the control of cell cycle and apoptosis at G2/M in normal and transformed epidermal keratinocytes.

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Faculty Opinions recommendation of Defective DNA repair and cell cycle arrest in cells expressing Merkel cell polyomavirus T antigen.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13692960.15107062 ◽

2012 ◽

Author(s):

Paul Nghiem ◽

Olga Afanasiev

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Cell Cycle Arrest ◽

T Antigen ◽

Merkel Cell Polyomavirus ◽

Merkel Cell ◽

Cycle Arrest ◽

Defective Dna Repair ◽

In Cells

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Role of Mis Localization of DNA Repair Factors in Cell Cycle Arrest

Biophysical Journal ◽

10.1016/j.bpj.2018.11.454 ◽

2019 ◽

Vol 116 (3) ◽

pp. 76a

Author(s):

Manasvita Vashisth ◽

Sangkyun Cho ◽

Dennis Discher

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Cell Cycle Arrest ◽

Cycle Arrest

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Involvement of the p38 MAPK signaling pathway in S-phase cell-cycle arrest induced by Furazolidone in human hepatoma G2 cells

Journal of Applied Toxicology ◽

10.1002/jat.2829 ◽

2012 ◽

Vol 33 (12) ◽

pp. 1500-1505 ◽

Cited By ~ 6

Author(s):

Yu Sun ◽

Shusheng Tang ◽

Xi Jin ◽

Chaoming Zhang ◽

Wenxia Zhao ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Signaling Pathway ◽

P38 Mapk ◽

Mapk Signaling ◽

S Phase ◽

Mapk Signaling Pathway ◽

Phase Cell ◽

Human Hepatoma ◽

Cycle Arrest

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A protein synthesis-dependent increase in E2F1 mRNA correlates with growth regulation of the dihydrofolate reductase promoter.

Molecular and Cellular Biology ◽

10.1128/mcb.13.3.1610 ◽

1993 ◽

Vol 13 (3) ◽

pp. 1610-1618 ◽

Cited By ~ 178

Author(s):

J E Slansky ◽

Y Li ◽

W G Kaelin ◽

P J Farnham

Keyword(s):

Cell Cycle ◽

Protein Synthesis ◽

Phase Boundary ◽

Dihydrofolate Reductase ◽

Transcription Initiation ◽

Growth Regulation ◽

Cellular Proliferation ◽

Protein S ◽

S Phase ◽

Dependent Manner

Enhanced expression of genes involved in nucleotide biosynthesis, such as dihydrofolate reductase (DHFR), is a hallmark of entrance into the DNA synthesis (S) phase of the mammalian cell cycle. To investigate the regulated expression of the DHFR gene, we stimulated serum-starved NIH 3T3 cells to synchronously reenter the cell cycle. Our previous results show that a cis-acting element at the site of DHFR transcription initiation is necessary for serum regulation. Recently, this element has been demonstrated to bind the cloned transcription factor E2F. In this study, we focused on the role of E2F in the growth regulation of DHFR. We demonstrated that a single E2F site, in the absence or presence of other promoter elements, was sufficient for growth-regulated promoter activity. Next, we showed that the increase in DHFR mRNA at the G1/S-phase boundary required protein synthesis, raising the possibility that a protein(s) lacking in serum-starved cells is required for DHFR transcription. We found that, similar to DHFR mRNA expression, levels of murine E2F1 mRNA were low in serum-starved cells and increased at the G1/S-phase boundary in a protein synthesis-dependent manner. Furthermore, in a cotransfection experiment, expression of human E2F1 stimulated the DHFR promoter 22-fold in serum-starved cells. We suggest that E2F1 may be the key protein required for DHFR transcription that is absent in serum-starved cells. Expression of E2F also abolished the serum-stimulated regulation of the DHFR promoter and resulted in transcription patterns similar to those seen with expression of the adenoviral oncoprotein E1A. In summary, we provide evidence for the importance of E2F in the growth regulation of DHFR and suggest that alterations in the levels of E2F may have severe consequences in the control of cellular proliferation.

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Cellular Senescence in Liver Disease and Regeneration

Seminars in Liver Disease ◽

10.1055/s-0040-1722262 ◽

2021 ◽

Author(s):

Sofia Ferreira-Gonzalez ◽

Daniel Rodrigo-Torres ◽

Victoria L. Gadd ◽

Stuart J. Forbes

Keyword(s):

Cell Cycle ◽

Liver Disease ◽

Cell Cycle Arrest ◽

Genomic Instability ◽

Cellular Senescence ◽

Cell Populations ◽

Cycle Arrest ◽

Relevant Role ◽

Extent Of Damage

AbstractCellular senescence is an irreversible cell cycle arrest implemented by the cell as a result of stressful insults. Characterized by phenotypic alterations, including secretome changes and genomic instability, senescence is capable of exerting both detrimental and beneficial processes. Accumulating evidence has shown that cellular senescence plays a relevant role in the occurrence and development of liver disease, as a mechanism to contain damage and promote regeneration, but also characterizing the onset and correlating with the extent of damage. The evidence of senescent mechanisms acting on the cell populations of the liver will be described including the role of markers to detect cellular senescence. Overall, this review intends to summarize the role of senescence in liver homeostasis, injury, disease, and regeneration.

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