P14ARF: The Absence that Makes the Difference

P14ARF is a tumor suppressor encoded by the CDKN2a locus that is frequently inactivated in human tumors. P14ARF protein quenches oncogene stimuli by inhibiting cell cycle progression and inducing apoptosis. P14ARF functions can be played through interactions with several proteins. However, the majority of its activities are notoriously mediated by the p53 protein. Interestingly, recent studies suggest a new role of p14ARF in the maintenance of chromosome stability. Here, we deepened this new facet of p14ARF which we believe is relevant to its tumor suppressive role in the cell. To this aim, we generated a monoclonal HCT116 cell line expressing the p14ARF cDNA cloned in the piggyback vector and then induced aneuploidy by treating HCT116 cells with the CENP-E inhibitor GSK923295. P14ARF ectopic re-expression restored the near-diploid phenotype of HCT116 cells, confirming that p14ARF counteracts aneuploid cell generation/proliferation.

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A Circular RNA from the MDM2 Locus Controls Cell Cycle Progression by Suppressing p53 Levels

Molecular and Cellular Biology ◽

10.1128/mcb.00473-19 ◽

2020 ◽

Vol 40 (9) ◽

Cited By ~ 4

Author(s):

Ritu Chaudhary ◽

Bruna R. Muys ◽

Ioannis Grammatikakis ◽

Supriyo De ◽

Kotb Abdelmohsen ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

P53 Protein ◽

Circular Rnas ◽

Small Interfering Rnas ◽

Cycle Progression ◽

Protein Levels

ABSTRACT Circular RNAs (circRNAs) are a class of noncoding RNAs produced by a noncanonical form of alternative splicing called back-splicing. To investigate a potential role of circRNAs in the p53 pathway, we analyzed RNA sequencing (RNA-seq) data from colorectal cancer cell lines (HCT116, RKO, and SW48) that were untreated or treated with a DNA-damaging agent. Surprisingly, unlike the strong p53-dependent induction of hundreds of p53-induced mRNAs upon DNA damage, only a few circRNAs were upregulated from p53-induced genes. circ-MDM2, an annotated circRNA from the MDM2 locus, was one of the handful of circRNAs that originated from a p53-induced gene. Given the central role of MDM2 in suppressing p53 protein levels and p53 activity, we investigated the function of circ-MDM2. Knocking down circ-MDM2 with small interfering RNAs (siRNAs) that targeted circ-MDM2 did not alter MDM2 mRNA or MDM2 protein levels but resulted in increased basal p53 levels and growth defects in vitro and in vivo. Consistent with these results, transcriptome profiling showed increased expression of several direct p53 targets, reduced retinoblastoma protein (Rb) phosphorylation, and defects in G1-S progression upon silencing circ-MDM2. Our results on the initial characterization of circ-MDM2 identify a new player from the MDM2 locus that suppresses p53 levels and cell cycle progression.

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PTTG has a Dual Role of Promotion-Inhibition in the Development of Pituitary Adenomas

Protein and Peptide Letters ◽

10.2174/0929866526666190722145449 ◽

2019 ◽

Vol 26 (11) ◽

pp. 800-818

Author(s):

Zujian Xiong ◽

Xuejun Li ◽

Qi Yang

Keyword(s):

Cell Cycle ◽

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Cell Cycle Progression ◽

Key Factors ◽

Cycle Progression ◽

Sister Chromatids ◽

Regulation Of Cell Cycle ◽

Late Stages

Pituitary Tumor Transforming Gene (PTTG) of human is known as a checkpoint gene in the middle and late stages of mitosis, and is also a proto-oncogene that promotes cell cycle progression. In the nucleus, PTTG works as securin in controlling the mid-term segregation of sister chromatids. Overexpression of PTTG, entering the nucleus with the help of PBF in pituitary adenomas, participates in the regulation of cell cycle, interferes with DNA repair, induces genetic instability, transactivates FGF-2 and VEGF and promotes angiogenesis and tumor invasion. Simultaneously, overexpression of PTTG induces tumor cell senescence through the DNA damage pathway, making pituitary adenoma possessing the potential self-limiting ability. To elucidate the mechanism of PTTG in the regulation of pituitary adenomas, we focus on both the positive and negative function of PTTG and find out key factors interacted with PTTG in pituitary adenomas. Furthermore, we discuss other possible mechanisms correlate with PTTG in pituitary adenoma initiation and development and the potential value of PTTG in clinical treatment.

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Interactions of Vascular Endothelial Growth Factor and p53 with miR-195 in Thyroid Carcinoma: Possible Therapeutic Targets in Aggressive Thyroid Cancers

Current Cancer Drug Targets ◽

10.2174/1568009618666180628154727 ◽

2019 ◽

Vol 19 (7) ◽

pp. 561-570 ◽

Cited By ~ 5

Author(s):

Hamidreza Maroof ◽

Soussan Irani ◽

Armin Arianna ◽

Jelena Vider ◽

Vinod Gopalan ◽

...

Keyword(s):

Cell Cycle ◽

Thyroid Carcinoma ◽

Cell Cycle Progression ◽

P53 Protein ◽

Carcinoma Cells ◽

Vascular Endothelial ◽

Papillary Thyroid ◽

Cycle Progression ◽

Thyroid Carcinomas ◽

Endothelial Growth Factor

Background: The clinical pathological features, as well as the cellular mechanisms of miR-195, have not been investigated in thyroid carcinoma. Objective: The aim of this study is to identify the interactions of vascular endothelial growth factor (VEGF), p53 and miR-195 in thyroid carcinoma. The clinical and pathological features of miR-195 were also investigated. Methods: The expression levels of miR-195 were identified in 123 primary thyroid carcinomas, 40 lymph nodes with metastatic papillary thyroid carcinomas and seven non-neoplastic thyroid tissues (controls) as well as two thyroid carcinoma cell lines, B-CPAP (from metastasizing human papillary thyroid carcinoma) and MB-1 (from anaplastic thyroid carcinoma), by the real-time polymerase chain reaction. Using Western blot and immunofluorescence, the effects of exogenous miR-195 on VEGF-A and p53 protein expression levels were examined. Then, cell cycle and apoptosis assays were performed to evaluate the roles of miR-195 in cell cycle progression and apoptosis. Results: The expression of miR-195 was downregulated in majority of the papillary thyroid carcinoma tissue as well as in cells. Introduction of exogenous miR-195 resulted in downregulation of VEGF-A and upregulation of p53 protein expressions. Upregulation of miR-195 in thyroid carcinoma cells resulted in cell cycle arrest. Moreover, we demonstrated that miR-195 inhibits cell cycle progression by induction of apoptosis in the thyroid carcinoma cells. Conclusion: Our findings showed for the first time that miR-195 acts as a tumour suppressor and regulates cell cycle progression and apoptosis by targeting VEGF-A and p53 in thyroid carcinoma. The current study exhibited that miR-195 might represent a potential therapeutic target for patients with thyroid carcinomas having aggressive clinical behaviour.

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Phosphorylation of RCC1 on Serine 11 Facilitates G1/S Transition in HPV E7-Expressing Cells

Biomolecules ◽

10.3390/biom11070995 ◽

2021 ◽

Vol 11 (7) ◽

pp. 995

Author(s):

Xiaoyan Hou ◽

Lijun Qiao ◽

Ruijuan Liu ◽

Xuechao Han ◽

Weifang Zhang

Keyword(s):

Cell Cycle ◽

Cervical Cancer ◽

Cell Cycle Regulation ◽

Cell Cycle Progression ◽

Mtor Pathway ◽

Cycle Progression ◽

Post Translational Modifications ◽

Hpv E7 ◽

Cycle Regulation

Persistent infection of high-risk human papillomavirus (HR-HPV) plays a causal role in cervical cancer. Regulator of chromosome condensation 1 (RCC1) is a critical cell cycle regulator, which undergoes a few post-translational modifications including phosphorylation. Here, we showed that serine 11 (S11) of RCC1 was phosphorylated in HPV E7-expressing cells. However, S11 phosphorylation was not up-regulated by CDK1 in E7-expressing cells; instead, the PI3K/AKT/mTOR pathway promoted S11 phosphorylation. Knockdown of AKT or inhibition of the PI3K/AKT/mTOR pathway down-regulated phosphorylation of RCC1 S11. Furthermore, S11 phosphorylation occurred throughout the cell cycle, and reached its peak during the mitosis phase. Our previous data proved that RCC1 was necessary for the G1/S cell cycle progression, and in the present study we showed that the RCC1 mutant, in which S11 was mutated to alanine (S11A) to mimic non-phosphorylation status, lost the ability to facilitate G1/S transition in E7-expressing cells. Moreover, RCC1 S11 was phosphorylated by the PI3K/AKT/mTOR pathway in HPV-positive cervical cancer SiHa and HeLa cells. We conclude that S11 of RCC1 is phosphorylated by the PI3K/AKT/mTOR pathway and phosphorylation of RCC1 S11 facilitates the abrogation of G1 checkpoint in HPV E7-expressing cells. In short, our study explores a new role of RCC1 S11 phosphorylation in cell cycle regulation.

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EGFR-ERK induced activation of GRHL1 promotes cell cycle progression by up-regulating cell cycle related genes in lung cancer

Cell Death and Disease ◽

10.1038/s41419-021-03721-9 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Yiming He ◽

Mingxi Gan ◽

Yanan Wang ◽

Tong Huang ◽

Jianbin Wang ◽

...

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Cell Cycle Progression ◽

Potential Role ◽

Target Genes ◽

Nuclear Translocation ◽

Phosphorylation Site ◽

Promoter Regions ◽

Cycle Progression

AbstractGrainyhead-like 1 (GRHL1) is a transcription factor involved in embryonic development. However, little is known about the biological functions of GRHL1 in cancer. In this study, we found that GRHL1 was upregulated in non-small cell lung cancer (NSCLC) and correlated with poor survival of patients. GRHL1 overexpression promoted the proliferation of NSCLC cells and knocking down GRHL1 inhibited the proliferation. RNA sequencing showed that a series of cell cycle-related genes were altered when knocking down GRHL1. We further demonstrated that GRHL1 could regulate the expression of cell cycle-related genes by binding to the promoter regions and increasing the transcription of the target genes. Besides, we also found that EGF stimulation could activate GRHL1 and promoted its nuclear translocation. We identified the key phosphorylation site at Ser76 on GRHL1 that is regulated by the EGFR-ERK axis. Taken together, these findings elucidate a new function of GRHL1 on regulating the cell cycle progression and point out the potential role of GRHL1 as a drug target in NSCLC.

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The nucleoplasmic interactions among Lamin A/C-pRB-LAP2α-E2F1 are modulated by dexamethasone

Scientific Reports ◽

10.1038/s41598-021-89608-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anastasia Ricci ◽

Sara Orazi ◽

Federica Biancucci ◽

Mauro Magnani ◽

Michele Menotta

Keyword(s):

Gene Expression ◽

Cell Cycle Progression ◽

Regulation Of Gene Expression ◽

Lamin A ◽

Wild Type ◽

Cycle Progression ◽

C Dynamics ◽

E2f Transcription Factor ◽

Transcription Factor 1

AbstractAtaxia telangiectasia (AT) is a rare genetic neurodegenerative disease. To date, there is no available cure for the illness, but the use of glucocorticoids has been shown to alleviate the neurological symptoms associated with AT. While studying the effects of dexamethasone (dex) in AT fibroblasts, by chance we observed that the nucleoplasmic Lamin A/C was affected by the drug. In addition to the structural roles of A-type lamins, Lamin A/C has been shown to play a role in the regulation of gene expression and cell cycle progression, and alterations in the LMNA gene is cause of human diseases called laminopathies. Dex was found to improve the nucleoplasmic accumulation of soluble Lamin A/C and was capable of managing the large chromatin Lamin A/C scaffolds contained complex, thus regulating epigenetics in treated cells. In addition, dex modified the interactions of Lamin A/C with its direct partners lamin associated polypeptide (LAP) 2a, Retinoblastoma 1 (pRB) and E2F Transcription Factor 1 (E2F1), regulating local gene expression dependent on E2F1. These effects were differentially observed in both AT and wild type (WT) cells. To our knowledge, this is the first reported evidence of the role of dex in Lamin A/C dynamics in AT cells, and may represent a new area of research regarding the effects of glucocorticoids on AT. Moreover, future investigations could also be extended to healthy subjects or to other pathologies such as laminopathies since glucocorticoids may have other important effects in these contexts as well.

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Mutations at sites involved in Suc1 binding inactivate Cdc2

Molecular and Cellular Biology ◽

10.1128/mcb.11.12.6177-6184.1991 ◽

1991 ◽

Vol 11 (12) ◽

pp. 6177-6184

Author(s):

B Ducommun ◽

P Brambilla ◽

G Draetta

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Specific Interaction ◽

Physiological Role ◽

Negative Effects ◽

Alanine Scanning Mutagenesis ◽

Cycle Progression ◽

Mutant Proteins ◽

Additional Protein

suc1+ encodes an essential cell cycle regulator of the fission yeast Schizosaccharomyces pombe. Its product, a 13-kDa protein, interacts with the Cdc2 protein kinase. Both positive and negative effects on cell cycle progression have been attributed to Suc1. To date, the exact mechanisms and the physiological role of the interaction between Suc1 and Cdc2 remain unclear. Here we have studied the molecular basis of this association. We show that Cdc2 can bind Suc1 or its mammalian homolog directly in the absence of any additional protein component. Using an alanine scanning mutagenesis method, we analyzed the interaction between Cdc2 and Suc1. We show that the integrity of several domains on the Cdc2 protein, including sites directly involved in catalytic activity, is required for binding to Suc1. Furthermore, Cdc2 mutant proteins unable to bind Suc1 (but able to bind cyclins) are nonfunctional when overexpressed in S. pombe, indicating that a specific interaction with Suc1 is required for Cdc2 function.

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Evidence for a role of spindle matrix formation in cell cycle progression by antibody perturbation

PLoS ONE ◽

10.1371/journal.pone.0208022 ◽

2018 ◽

Vol 13 (11) ◽

pp. e0208022 ◽

Cited By ~ 2

Author(s):

Changfu Yao ◽

Chao Wang ◽

Yeran Li ◽

Michael Zavortink ◽

Vincent Archambault ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Spindle Matrix

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Role of AKT/mTORC1 pathway in pancreatic β-cell proliferation

Colombia Medica ◽

10.25100/cm.v43i3.783 ◽

2012 ◽

pp. 235-243 ◽

Cited By ~ 9

Author(s):

Norman Balcazar Morales ◽

Cecilia Aguilar de Plata

Keyword(s):

Cell Cycle ◽

Growth Factors ◽

Cell Cycle Progression ◽

Cell Mass ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cycle Progression ◽

Mtorc1 Signaling

Growth factors, insulin signaling and nutrients are important regulators of β-cell mass and function. The events linking these signals to regulation of β-cell mass are not completely understood. Recent findings indicate that mTOR pathway integrates signals from growth factors and nutrients with transcription, translation, cell size, cytoskeleton remodeling and mitochondrial metabolism. mTOR is a part of two distinct complexes; mTORC1 and mTORC2. The mammalian TORC1 is sensitive to rapamycin and contains Raptor, deptor, PRAS40 and the G protein β-subunit-like protein (GβL). mTORC1 activates key regulators of protein translation; ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E-binding protein 1. This review summarizes current findings about the role of AKT/mTORC1 signaling in regulation of pancreatic β cell mass and proliferation. mTORC1 is a major regulator of β-cell cycle progression by modulation of cyclins D2, D3 and cdk4/cyclin D activity. These studies uncovered key novel pathways controlling cell cycle progression in β-cells in vivo. This information can be used to develop alternative approaches to expand β-cell mass in vivo and in vitro without the risk of oncogenic transformation. The acquisition of such knowledge is critical for the design of improved therapeutic strategies for the treatment and cure of diabetes as well as to understand the effects of mTOR inhibitors in β-cell function.

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