Hippo signaling is intrinsically regulated during cell cycle progression by APC/CCdh1

The Hippo-YAP/TAZ signaling pathway plays a pivotal role in growth control during development and regeneration and its dysregulation is widely implicated in various cancers. To further understand the cellular and molecular mechanisms underlying Hippo signaling regulation, we have found that activities of core Hippo signaling components, large tumor suppressor (LATS) kinases and YAP/TAZ transcription factors, oscillate during mitotic cell cycle. We further identified that the anaphase-promoting complex/cyclosome (APC/C)Cdh1 E3 ubiquitin ligase complex, which plays a key role governing eukaryotic cell cycle progression, intrinsically regulates Hippo signaling activities. CDH1 recognizes LATS kinases to promote their degradation and, hence, YAP/TAZ regulation by LATS phosphorylation is under cell cycle control. As a result, YAP/TAZ activities peak in G1 phase. Furthermore, we show in Drosophila eye and wing development that Cdh1 is required in vivo to regulate the LATS homolog Warts with a conserved mechanism. Cdh1 reduction increased Warts levels, which resulted in reduction of the eye and wing sizes in a Yorkie dependent manner. Therefore, LATS degradation by APC/CCdh1 represents a previously unappreciated and evolutionarily conserved layer of Hippo signaling regulation.

Download Full-text

Molecular Mechanisms Underlying Yatein-Induced Cell-Cycle Arrest and Microtubule Destabilization in Human Lung Adenocarcinoma Cells

Cancers ◽

10.3390/cancers11091384 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1384 ◽

Cited By ~ 3

Author(s):

Shang-Tse Ho ◽

Chi-Chen Lin ◽

Yu-Tang Tung ◽

Jyh-Horng Wu

Keyword(s):

Cell Cycle ◽

Antitumor Activity ◽

Lung Adenocarcinoma ◽

Cell Cycle Progression ◽

Molecular Mechanisms ◽

Human Lung ◽

Microtubule Dynamics ◽

Cycle Progression ◽

Human Lung Adenocarcinoma

Yatein is an antitumor agent isolated from Calocedrus formosana Florin leaves extract. In our previous study, we found that yatein inhibited the growth of human lung adenocarcinoma A549 and CL1-5 cells by inducing intrinsic and extrinsic apoptotic pathways. To further uncover the effects and mechanisms of yatein-induced inhibition on A549 and CL1-5 cell growth, we evaluated yatein-mediated antitumor activity in vivo and the regulatory effects of yatein on cell-cycle progression and microtubule dynamics. Flow cytometry and western blotting revealed that yatein induces G2/M arrest in A549 and CL1-5 cells. Yatein also destabilized microtubules and interfered with microtubule dynamics in the two cell lines. Furthermore, we evaluated the antitumor activity of yatein in vivo using a xenograft mouse model and found that yatein treatment altered cyclin B/Cdc2 complex expression and significantly inhibited tumor growth. Taken together, our results suggested that yatein effectively inhibited the growth of A549 and CL1-5 cells possibly by disrupting cell-cycle progression and microtubule dynamics.

Download Full-text

Lamina-associated polypeptide 2α regulates cell cycle progression and differentiation via the retinoblastoma–E2F pathway

The Journal of Cell Biology ◽

10.1083/jcb.200511149 ◽

2006 ◽

Vol 173 (1) ◽

pp. 83-93 ◽

Cited By ~ 98

Author(s):

Daniela Dorner ◽

Sylvia Vlcek ◽

Nicole Foeger ◽

Andreas Gajewski ◽

Christian Makolm ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Target Genes ◽

Serum Starvation ◽

Dependent Manner ◽

Cycle Progression ◽

Promoter Sequences ◽

Delayed Entry ◽

Accelerated Proliferation

Lamina-associated polypeptide (LAP) 2α is a nonmembrane-bound LAP2 isoform that forms complexes with nucleoplasmic A-type lamins. In this study, we show that the overexpression of LAP2α in fibroblasts reduced proliferation and delayed entry into the cell cycle from a G0 arrest. In contrast, stable down-regulation of LAP2α by RNA interference accelerated proliferation and interfered with cell cycle exit upon serum starvation. The LAP2α-linked cell cycle phenotype is mediated by the retinoblastoma (Rb) protein because the LAP2α COOH terminus directly bound Rb, and overexpressed LAP2α inhibited E2F/Rb-dependent reporter gene activity in G1 phase in an Rb-dependent manner. Furthermore, LAP2α associated with promoter sequences in endogenous E2F/Rb-dependent target genes in vivo and negatively affected their expression. In addition, the expression of LAP2α in proliferating preadipocytes caused the accumulation of hypophosphorylated Rb, which is reminiscent of noncycling cells, and initiated partial differentiation into adipocytes. The effects of LAP2α on cell cycle progression and differentiation may be highly relevant for the cell- and tissue-specific phenotypes observed in laminopathic diseases.

Download Full-text

C-terminal domain phosphorylation of ERK3 controlled by Cdk1 and Cdc14 regulates its stability in mitosis

Biochemical Journal ◽

10.1042/bj20091604 ◽

2010 ◽

Vol 428 (1) ◽

pp. 103-111 ◽

Cited By ~ 16

Author(s):

Pierre-Luc Tanguay ◽

Geneviève Rodier ◽

Sylvain Meloche

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Mitotic Cell ◽

Mitogen Activated Protein Kinase ◽

Phosphorylation Sites ◽

Dependent Manner ◽

Cell Extracts ◽

Cycle Dependent

ERK3 (extracellular-signal-regulated kinase 3) is an atypical MAPK (mitogen-activated protein kinase) that is suggested to play a role in cell-cycle progression and cellular differentiation. However, it is not known whether the function of ERK3 is regulated during the cell cycle. In the present paper, we report that ERK3 is stoichiometrically hyperphosphorylated during entry into mitosis and is dephosphorylated at the M→G1 transition. The phosphorylation of ERK3 is associated with the accumulation of the protein in mitosis. In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. All four sites are followed by a proline residue. We have shown that purified cyclin B-Cdk1 (cyclindependent kinase 1) phosphorylates these sites in vitro and demonstrate that Cdk1 acts as a major Thr698 kinase in vivo. Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. The results of the present study identify a novel regulatory mechanism of ERK3 that operates in a cell-cycle-dependent manner.

Download Full-text

Natural sourced inhibitors of EGFR, PDGFR, FGFR and VEGFR-mediated signaling pathways as potential anticancer agents

Current Medicinal Chemistry ◽

10.2174/0929867328666210303101345 ◽

2021 ◽

Vol 28 ◽

Author(s):

Sisir Nandi ◽

Rishita Dey ◽

Asmita Samadder ◽

Aaruni Saxena ◽

Anil Kumar Saxena

Keyword(s):

Cell Cycle ◽

Cancer Progression ◽

Anticancer Agents ◽

Cell Cycle Progression ◽

Molecular Mechanisms ◽

Mitotic Cell ◽

Cell Cycle Checkpoints ◽

Signalling Pathways ◽

Mitotic Cell Cycle ◽

Cycle Progression

: The molecular mechanisms of mitotic cell cycle progression involve very tightly restricted types of machinery which are highly regulated by a fine balance between the positive and negative accelerators (or regulators). These regulators include several checkpoints that have proteins acting as enzymes and their activating partners. These checkpoints incessantly monitor the external as well as internal environments such as growth signals, favorable conditions for growth, cell size, DNA integrity of the cell and hence function to maintain the highly ordered cell cycle progression by sustaining cell homeostasis and promotes error-free DNA replication and cell cycle, division. To progress through the mitotic cell cycle, the cell has to successfully drive past the cell cycle checkpoints. Due to the abnormal behavior of some cell cycle proteins, the cells tend to divide continuously overcoming the tight regulation of cell cycle checkpoints. Such anomalies may lead to unwanted cell division and this deregulation of cell cycle events is considered as one of the main reasons behind tumor development and thus cancer progression. So the understanding of the molecular mechanisms in cancer progression might be insightful for designing several cancer treatment strategies. The deregulation in the checkpoints is caused due to the changes brought in the tyrosine residues of TPKs via PDGFR, EGFR, FGFR, and VEGFR-mediated signalling pathways. Therefore, the inhibitors of PDGFR, EGFR, FGFR, and VEGFR-mediated signalling pathways would be potential anticancer agents. The resistance and toxicity in the existing synthetic anticancer chemotherapeutics may decrease the life span of a patient. For a long, natural products have always played an essential alternative source of therapeutic agents due to having the least or no side effect and toxicity. The present study is an attempt to promote the natural anticancer drug development focusing on the updated structural information of PDGFR, EGFR, FGFR, and VEGFR inhibitors isolated from the plant sources. The data used in this review has been collected from internet resources viz. GOOGLE Web, GOOGLE SCHOLAR, and PubMed Central. The citation of each report was first checked after which the articles were selected as an authentic reference for the present study. Around 200 journal articles were selected of which around 142 were selected finally for presenting the study on the natural sourced inhibitors of EGFR, PDGFR, FGFR, and VEGFR-mediated signaling pathways which would help in the potential cancer treatment.

Download Full-text

Wogonin Induces Cell Cycle Arrest and Apoptosis of Hepatocellular Carcinoma Cells by Activating Hippo Signalling

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210824105915 ◽

2021 ◽

Vol 21 ◽

Author(s):

Keyan Wu ◽

Man Teng ◽

Wei Zhou ◽

Fanglin Lu ◽

Yang Zhou ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Cell Cycle Progression ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Hippo Signaling ◽

Rna Seq ◽

Cycle Progression ◽

Cycle Arrest ◽

Hcc Cells

Objective: The current study aimed to illustrate whether wogonin influences HCC cell cycle progression and apoptosis by regulating Hippo signaling. Methods: The effects of wogonin on HCC cell viability, cell cycle progression and apoptosis were analyzed by utilizing CCK-8 and flow cytometry. RNA-seq was employed to analyze the expression profiles between wogonin-treated and control HCC cells, and the selected RNA-seq transcripts were validated by reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR). Immunofluorescence staining was performed to detect the distribution of YAP/TAZ in the nucleus and cytoplasm in HCC cells. Western blotting and human apoptosis array were performed to examine the expression of the indicated genes. Results: We demonstrated that wogonin induced cell cycle arrest and apoptosis of HCC cell lines SMMC7721 and HCCLM3. RNA-seq analysis showed enrichment in genes associated with cell cycle progression and apoptosis following incubation with wogonin in HCC cells, and the pathways analysis further identified that Hippo signaling pathways highly altered in wogonin-treated cells. Specifically, wogonin increased the phosphorylation of MOB1 and LATS1, promoted translocation of endogenous YAP and TAZ from the nucleus to the cytoplasm, and facilitated phosphorylation of YAP and TAZ. Notably, overexpression of YAP or TAZ partially abrogated the wogonin-mediated HCC cell cycle arrest and apoptosis, and reversed wogonin-mediated suppression of Claspin. Conclusion: Wogonin induced HCC cell cycle arrest and apoptosis probably by activating MOB1-LATS1 signaling to inhibit the activation of YAP and TAZ, and then decrease the expression of Claspin, suggesting that the understanding of the molecular mechanisms underlying wogonin-induced cell cycle arrest and apoptosis may be useful in HCC therapeutics.

Download Full-text

SATB2-AS1 acts as miR-299-3p sponge to facilitate tumorigenesis in human non-small cell lung cancer

Archives of Medical Science ◽

10.5114/aoms/119168 ◽

2021 ◽

Author(s):

Xiaofeng Wu ◽

Junti Lu ◽

Wen Chen ◽

Meng Liang ◽

Nan Wang ◽

...

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Tumor Cell ◽

Cell Cycle Progression ◽

Molecular Mechanisms ◽

Tumor Cell Proliferation ◽

Small Cell Lung ◽

Cycle Progression

IntroductionNon-small cell lung cancer (NSCLC), the most common pathological type of lung cancer, is partly responsible for an increasing number of tumor-related deaths worldwide. This study aimed to explore the biological role of the anti-sense transcript of special AT-rich sequence binding protein 2 (SATB2-AS1), a novel cancer-related long non-coding RNA (lncRNA), and illustrate the potential molecular mechanisms.Material and methodsThe expression patterns of SATB2-AS1 were determined via qPCR analysis in clinical samples and tumor cell lines. Kaplan-Meier survival analysis was conducted to assess the relationship between SATB2-AS1 expression and survival time of NSCLC patients. NSCLC tumors were transfected with SATB2-AS1 expression vectors or specific short hairpin RNAs (sh-SATB2-AS1). Tumor cell proliferation, cell cycle progression and apoptosis was detected by MTT assays and flow cytometric method, respectively. Nude mouse transplantation models were applied to investigate the effects of SATB2-AS1 on tumor cell growth in vivo. Bio-informatics analysis, luciferase reporter assays and rescue assays were performed to elucidate possible molecular mechanisms.ResultsSATB2-AS1 up-regulation was observed in tumorous tissues and cell lines. Up-regulated SATB2-AS1 expression was associated with shorter overall survival time of patients. SATB2-AS1 over-expression facilitated tumor cell proliferation, cell cycle progression and survival, while its knockdown inhibited tumor cell proliferation, cell cycle progression and survival. SATB2-AS1 depletion suppressed tumor growth in vivo. SATB2-AS1 was revealed to act as a miR-299-3p sponge to exert carcinogenic role.ConclusionsOur data indicate that SATB2-AS1 acts as a miR-299-3p sponge to facilitate NSCLC development, providing a novel candidate therapeutic target for NSCLC.

Download Full-text

LMNB2 promotes the progression of colorectal cancer by silencing p21 expression

Cell Death and Disease ◽

10.1038/s41419-021-03602-1 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Chen-Hua Dong ◽

Tao Jiang ◽

Hang Yin ◽

Hu Song ◽

Yi Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Cell Cycle Progression ◽

Molecular Mechanisms ◽

Gene Set Enrichment Analysis ◽

Molecular Therapy ◽

Cycle Progression ◽

Cancer Tissues

AbstractColorectal cancer is the second common cause of death worldwide. Lamin B2 (LMNB2) is involved in chromatin remodeling and the rupture and reorganization of nuclear membrane during mitosis, which is necessary for eukaryotic cell proliferation. However, the role of LMNB2 in colorectal cancer (CRC) is poorly understood. This study explored the biological functions of LMNB2 in the progression of colorectal cancer and explored the possible molecular mechanisms. We found that LMNB2 was significantly upregulated in primary colorectal cancer tissues and cell lines, compared with paired non-cancerous tissues and normal colorectal epithelium. The high expression of LMNB2 in colorectal cancer tissues is significantly related to the clinicopathological characteristics of the patients and the shorter overall and disease-free cumulative survival. Functional analysis, including CCK8 cell proliferation test, EdU proliferation test, colony formation analysis, nude mouse xenograft, cell cycle, and apoptosis analysis showed that LMNB2 significantly promotes cell proliferation by promoting cell cycle progression in vivo and in vitro. In addition, gene set enrichment analysis, luciferase report analysis, and CHIP analysis showed that LMNB2 promotes cell proliferation by regulating the p21 promoter, whereas LMNB2 has no effect on cell apoptosis. In summary, these findings not only indicate that LMNB2 promotes the proliferation of colorectal cancer by regulating p21-mediated cell cycle progression, but also suggest the potential value of LMNB2 as a clinical prognostic marker and molecular therapy target.

Download Full-text

To Divide or Not to Divide? How Deuterium Affects Growth and Division of Chlamydomonas reinhardtii

Biomolecules ◽

10.3390/biom11060861 ◽

2021 ◽

Vol 11 (6) ◽

pp. 861

Author(s):

Veronika Kselíková ◽

Vilém Zachleder ◽

Kateřina Bišová

Keyword(s):

Cell Cycle ◽

Chlamydomonas Reinhardtii ◽

Cell Cycle Progression ◽

Model Organism ◽

Cycle Progression ◽

Synchronous Cultures ◽

Multiple Fission ◽

First Choice ◽

High Doses

Extensive in vivo replacement of hydrogen by deuterium, a stable isotope of hydrogen, induces a distinct stress response, reduces cell growth and impairs cell division in various organisms. Microalgae, including Chlamydomonas reinhardtii, a well-established model organism in cell cycle studies, are no exception. Chlamydomonas reinhardtii, a green unicellular alga of the Chlorophyceae class, divides by multiple fission, grows autotrophically and can be synchronized by alternating light/dark regimes; this makes it a model of first choice to discriminate the effect of deuterium on growth and/or division. Here, we investigate the effects of high doses of deuterium on cell cycle progression in C. reinhardtii. Synchronous cultures of C. reinhardtii were cultivated in growth medium containing 70 or 90% D2O. We characterize specific deuterium-induced shifts in attainment of commitment points during growth and/or division of C. reinhardtii, contradicting the role of the “sizer” in regulating the cell cycle. Consequently, impaired cell cycle progression in deuterated cultures causes (over)accumulation of starch and lipids, suggesting a promising potential for microalgae to produce deuterated organic compounds.

Download Full-text

Analysis of Cell Cycle and Replication of Mouse Macrophages afterIn VivoandIn VitroCryptococcus neoformans Infection Using Laser Scanning Cytometry

Infection and Immunity ◽

10.1128/iai.06332-11 ◽

2012 ◽

Vol 80 (4) ◽

pp. 1467-1478 ◽

Cited By ~ 12

Author(s):

Carolina Coelho ◽

Lydia Tesfa ◽

Jinghang Zhang ◽

Johanna Rivera ◽

Teresa Gonçalves ◽

...

Keyword(s):

Cell Cycle ◽

Cell Division ◽

Cytotoxic Effect ◽

Laser Scanning ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Content Type ◽

Cycle Arrest ◽

Laser Scanning Cytometry

ABSTRACTWe investigated the outcome of the interaction ofCryptococcus neoformanswith murine macrophages using laser scanning cytometry (LSC). Previous results in our lab had shown that phagocytosis ofC. neoformanspromoted cell cycle progression. LSC allowed us to simultaneously measure the phagocytic index, macrophage DNA content, and 5-ethynyl-2′-deoxyuridine (EdU) incorporation such that it was possible to study host cell division as a function of phagocytosis. LSC proved to be a robust, reliable, and high-throughput method for quantifying phagocytosis. Phagocytosis ofC. neoformanspromoted cell cycle progression, but infected macrophages were significantly less likely to complete mitosis. Hence, we report a new cytotoxic effect associated with intracellularC. neoformansresidence that manifested itself in impaired cell cycle completion as a consequence of a block in the G2/M stage of the mitotic cell cycle. Cell cycle arrest was not due to increased cell membrane permeability or DNA damage. We investigated alveolar macrophage replicationin vivoand demonstrated that these cells are capable of low levels of cell division in the presence or absence ofC. neoformansinfection. In summary, we simultaneously studied phagocytosis, the cell cycle state of the host cell and pathogen-mediated cytotoxicity, and our results demonstrate a new cytotoxic effect ofC. neoformansinfection on murine macrophages: fungus-induced cell cycle arrest. Finally, we provide evidence for alveolar macrophage proliferationin vivo.

Download Full-text

A bulky glycocalyx fosters metastasis formation by promoting G1 cell cycle progression

eLife ◽

10.7554/elife.25752 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 27

Author(s):

Elliot C Woods ◽

FuiBoon Kai ◽

J Matthew Barnes ◽

Kayvon Pedram ◽

Michael W Pickup ◽

...

Keyword(s):

Cell Cycle ◽

Tumor Cells ◽

Cell Cycle Progression ◽

Disseminated Tumor Cells ◽

Metastatic Potential ◽

Cancer Cell Growth ◽

Cycle Progression ◽

Growth And Survival ◽

Syngeneic Mouse Model

Metastasis depends upon cancer cell growth and survival within the metastatic niche. Tumors which remodel their glycocalyces, by overexpressing bulky glycoproteins like mucins, exhibit a higher predisposition to metastasize, but the role of mucins in oncogenesis remains poorly understood. Here we report that a bulky glycocalyx promotes the expansion of disseminated tumor cells in vivo by fostering integrin adhesion assembly to permit G1 cell cycle progression. We engineered tumor cells to display glycocalyces of various thicknesses by coating them with synthetic mucin-mimetic glycopolymers. Cells adorned with longer glycopolymers showed increased metastatic potential, enhanced cell cycle progression, and greater levels of integrin-FAK mechanosignaling and Akt signaling in a syngeneic mouse model of metastasis. These effects were mirrored by expression of the ectodomain of cancer-associated mucin MUC1. These findings functionally link mucinous proteins with tumor aggression, and offer a new view of the cancer glycocalyx as a major driver of disease progression.

Download Full-text