MODEL-BASED IDENTIFICATION AND ADAPTIVE CONTROL OF THE CORE MODULE IN A TYPICAL CELL CYCLE PATHWAY VIA NETWORK AND SYSTEM CONTROL THEORIES

2009 ◽  
Vol 12 (01) ◽  
pp. 21-43 ◽  
Author(s):  
BINHUA TANG ◽  
LI HE ◽  
QING JING ◽  
BAIRONG SHEN
Keyword(s):  
Cell Cycle ◽  
Adaptive Control ◽  
Molecular Mechanisms ◽  
Cell Cycle Control ◽  
System Control ◽  
Core Module ◽  
Typical Cell ◽  
And Performance ◽  
Control Theories

The loss of cell cycle control is often associated with cancers and other different diseases. With the accumulation of omics data, the network for molecule interactions in the cell cycle process will become much clearer. The identification of the crucial modules in a giant network and investigation of inherent control relations are very important to the understanding of the molecular mechanisms of diseases for new drug design. The paper proposes novel techniques in analyzing such core regulatory modules based on network and system control theories. We initially define the degree of participation (DOP) and the rate of activity (ROA) for indentifying core module components, and then the diverse contribution elasticity functions for quantifying pairwise regulatory or control activities between those components, thus facilitating the decomposition of expanded core modules and the formation of feedback loops within the control schema. Motivated by the inherent regulatory mechanisms, we expound a kind of multiphase nonlinear adaptive control algorithm in repelling abnormal genetic mutations, which directly and indirectly impact cancer development in biological cells and organs. Experimental predictions are also elucidated within the work, helping those in vivo design, verification and performance evaluation.

Mitosis-specific phosphorylation of nucleolin by p34cdc2 protein kinase

1990 ◽  
Vol 10 (7) ◽  
pp. 3607-3618
Author(s):  
P Belenguer ◽  
M Caizergues-Ferrer ◽  
J C Labbé ◽  
M Dorée ◽  
F Amalric
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Control ◽  
Nucleolar Organizer ◽  
Serine Phosphorylation ◽  
Nucleolar Organizer Regions ◽  
Rdna Transcription ◽  
Amino Terminal ◽  
Nucleolar Chromatin

Nucleolin is a ubiquitous multifunctional protein involved in preribosome assembly and associated with both nucleolar chromatin in interphase and nucleolar organizer regions on metaphasic chromosomes in mitosis. Extensive nucleolin phosphorylation by a casein kinase (CKII) occurs on serine in growing cells. Here we report that while CKII phosphorylation is achieved in interphase, threonine phosphorylation occurs during mitosis. We provide evidence that this type of in vivo phosphorylation involves a mammalian homolog of the cell cycle control Cdc2 kinase. In vitro M-phase H1 kinase from starfish oocytes phosphorylated threonines in a TPXK motif present nine times in the amino-terminal part of the protein. The same sites which matched the p34cdc2 consensus phosphorylation sequence were used in vivo during mitosis. We propose that successive Cdc2 and CKII phosphorylation could modulate nucleolin function in controlling cell cycle-dependent nucleolar function and organization. Our results, along with previous studies, suggest that while serine phosphorylation is related to nucleolin function in the control of rDNA transcription, threonine phosphorylation is linked to mitotic reorganization of nucleolar chromatin.

scholarly journals Positive feedback between lncRNA FLVCR1-AS1 and KLF10 may inhibit pancreatic cancer progression via the PTEN/AKT pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jiewei Lin ◽  
Shuyu Zhai ◽  
Siyi Zou ◽  
Zhiwei Xu ◽  
Jun Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Positive Feedback ◽  
Molecular Mechanisms ◽  
Tumor Tissues ◽  
And Migration

Abstract Background FLVCR1-AS1 is a key regulator of cancer progression. However, the biological functions and underlying molecular mechanisms of pancreatic cancer (PC) remain unknown. Methods FLVCR1-AS1 expression levels in 77 PC tissues and matched non-tumor tissues were analyzed by qRT-PCR. Moreover, the role of FLVCR1-AS1 in PC cell proliferation, cell cycle, and migration was verified via functional in vitro and in vivo experiments. Further, the potential competitive endogenous RNA (ceRNA) network between FLVCR1-AS1 and KLF10, as well as FLVCR1-AS1 transcription levels, were investigated. Results FLVCR1-AS1 expression was low in both PC tissues and PC cell lines, and FLVCR1-AS1 downregulation was associated with a worse prognosis in patients with PC. Functional experiments demonstrated that FLVCR1-AS1 overexpression significantly suppressed PC cell proliferation, cell cycle, and migration both in vitro and in vivo. Mechanistic investigations revealed that FLVCR1-AS1 acts as a ceRNA to sequester miR-513c-5p or miR-514b-5p from the sponging KLF10 mRNA, thereby relieving their suppressive effects on KLF10 expression. Additionally, FLVCR1-AS1 was shown to be a direct transcriptional target of KLF10. Conclusions Our research suggests that FLVCR1-AS1 plays a tumor-suppressive role in PC by inhibiting proliferation, cell cycle, and migration through a positive feedback loop with KLF10, thereby providing a novel therapeutic strategy for PC treatment.

scholarly journals Protein Kinase C Signaling Mediates a Program of Cell Cycle Withdrawal in the Intestinal Epithelium

2000 ◽  
Vol 151 (4) ◽  
pp. 763-778 ◽  
Author(s):  
Mark R. Frey ◽  
Jennifer A. Clark ◽  
Olga Leontieva ◽  
Joshua M. Uronis ◽  
Adrian R. Black ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Intestinal Epithelium ◽  
Molecular Mechanisms ◽  
Model Systems ◽  
Intestinal Epithelial ◽  
Kinase C

Members of the protein kinase C (PKC) family of signal transduction molecules have been widely implicated in regulation of cell growth and differentiation, although the underlying molecular mechanisms involved remain poorly defined. Using combined in vitro and in vivo intestinal epithelial model systems, we demonstrate that PKC signaling can trigger a coordinated program of molecular events leading to cell cycle withdrawal into G0. PKC activation in the IEC-18 intestinal crypt cell line resulted in rapid downregulation of D-type cyclins and differential induction of p21waf1/cip1 and p27kip1, thus targeting all of the major G1/S cyclin-dependent kinase complexes. These events were associated with coordinated alterations in expression and phosphorylation of the pocket proteins p107, pRb, and p130 that drive cells to exit the cell cycle into G0 as indicated by concomitant downregulation of the DNA licensing factor cdc6. Manipulation of PKC isozyme levels in IEC-18 cells demonstrated that PKCα alone can trigger hallmark events of cell cycle withdrawal in intestinal epithelial cells. Notably, analysis of the developmental control of cell cycle regulatory molecules along the crypt–villus axis revealed that PKCα activation is appropriately positioned within intestinal crypts to trigger this program of cell cycle exit–specific events in situ. Together, these data point to PKCα as a key regulator of cell cycle withdrawal in the intestinal epithelium.

scholarly journals Tumor quiescence: elevating SOX2 in diverse tumor cell types downregulates a broad spectrum of the cell cycle machinery and inhibits tumor growth

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ethan P. Metz ◽  
Erin L. Wuebben ◽  
Phillip J. Wilder ◽  
Jesse L. Cox ◽  
Kaustubh Datta ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cell Cycle Machinery

Abstract Background Quiescent tumor cells pose a major clinical challenge due to their ability to resist conventional chemotherapies and to drive tumor recurrence. Understanding the molecular mechanisms that promote quiescence of tumor cells could help identify therapies to eliminate these cells. Significantly, recent studies have determined that the function of SOX2 in cancer cells is highly dose dependent. Specifically, SOX2 levels in tumor cells are optimized to promote tumor growth: knocking down or elevating SOX2 inhibits proliferation. Furthermore, recent studies have shown that quiescent tumor cells express higher levels of SOX2 compared to adjacent proliferating cells. Currently, the mechanisms through which elevated levels of SOX2 restrict tumor cell proliferation have not been characterized. Methods To understand how elevated levels of SOX2 restrict the proliferation of tumor cells, we engineered diverse types of tumor cells for inducible overexpression of SOX2. Using these cells, we examined the effects of elevating SOX2 on their proliferation, both in vitro and in vivo. In addition, we examined how elevating SOX2 influences their expression of cyclins, cyclin-dependent kinases (CDKs), and p27Kip1. Results Elevating SOX2 in diverse tumor cell types led to growth inhibition in vitro. Significantly, elevating SOX2 in vivo in pancreatic ductal adenocarcinoma, medulloblastoma, and prostate cancer cells induced a reversible state of tumor growth arrest. In all three tumor types, elevation of SOX2 in vivo quickly halted tumor growth. Remarkably, tumor growth resumed rapidly when SOX2 returned to endogenous levels. We also determined that elevation of SOX2 in six tumor cell lines decreased the levels of cyclins and CDKs that control each phase of the cell cycle, while upregulating p27Kip1. Conclusions Our findings indicate that elevating SOX2 above endogenous levels in a diverse set of tumor cell types leads to growth inhibition both in vitro and in vivo. Moreover, our findings indicate that SOX2 can function as a master regulator by controlling the expression of a broad spectrum of cell cycle machinery. Importantly, our SOX2-inducible tumor studies provide a novel model system for investigating the molecular mechanisms by which elevated levels of SOX2 restrict cell proliferation and tumor growth.

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

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1384 ◽  
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.

scholarly journals Cell Cycle Kinase Polo Is Controlled by a Widespread 3′ Untranslated Region Regulatory Sequence inDrosophila melanogaster

2019 ◽  
Vol 39 (15) ◽  
Author(s):  
Marta S. Oliveira ◽  
Jaime Freitas ◽  
Pedro A. B. Pinto ◽  
Ana de Jesus ◽  
Joana Tavares ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Drosophila Melanogaster ◽  
Untranslated Region ◽  
Molecular Mechanisms ◽  
Alternative Polyadenylation ◽  
Upstream Sequence ◽  
Sequence Element ◽  
Content Type ◽  
Cell Cycle Kinase

ABSTRACTAlternative polyadenylation generates transcriptomic diversity, although the physiological impact and regulatory mechanisms involved are still poorly understood. The cell cycle kinase Polo is controlled by alternative polyadenylation in the 3′ untranslated region (3′UTR), with critical physiological consequences. Here, we characterized the molecular mechanisms required forpoloalternative polyadenylation. We identified a conserved upstream sequence element (USE) close to thepoloproximal poly(A) signal. Transgenic flies without this sequence show incorrect selection ofpolopoly(A) signals with consequent downregulation of Polo expression levels and insufficient/defective activation of Polo kinetochore targets Mps1 and Aurora B. Deletion of the USE results in abnormal mitoses in neuroblasts, revealing a role for this sequencein vivo. We found that Hephaestus binds to the USE RNA and thathephaestusmutants display defects inpoloalternative polyadenylation concomitant with a striking reduction in Polo protein levels, leading to mitotic errors and aneuploidy. Bioinformatic analyses show that the USE is preferentially localized upstream of noncanonical polyadenylation signals inDrosophila melanogastergenes. Taken together, our results revealed the molecular mechanisms involved inpoloalternative polyadenylation, with remarkable physiological functions in Polo expression and activity at the kinetochores, and disclosed a newin vivofunction for USEs inDrosophila melanogaster.

Genomic landscape of HBV-related hepatocellular carcinoma in south China patients with high mutational frequency of TP53 and TERT promoter.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15670-e15670
Author(s):  
Jiazhou Ye ◽  
Yinguang Wang ◽  
Rong Liang ◽  
Xue Wu ◽  
Yang Shao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Wnt Signaling ◽  
South China ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Biological Effects ◽  
Cell Cycle Control ◽  
Tert Promoter ◽  
Genomic Landscape

e15670 Background: Development of hepatocellular carcinoma (HCC) is a complex process with accumulations of polygene abnormalities and multi-pathway misregulation. Hepatitis B virus (HBV) exposure can cause liver damage and promote hepatocarcinogenesis via various biological effects. We aimed to investigate the molecular mechanisms underlying the etiology of HBV-related HCC development, and provide new insights into novel molecular targets. Methods: 84 HBV-positive HCC patients from Guangxi Province, South China, who underwent hepatic resection, were enrolled in this study. Genomic alterations were analyzed in pair-matched tumor and adjacent normal tissue using a hybridization capture-based next-generation sequencing (NGS) assay targeting 422 cancer-relevant genes. Results: In total, 691 somatic mutations, 166 copy number variations and 10 gene fusions were detected in 81 (96.4%) of 84 tumor samples. The most commonly mutated gene is TP53 in this cohort (84% of the patients), which is much higher than its frequency in the reported overall HCC patients. TERT promoter has somatic mutations in 32% of the patients, reactivation of which has been implicated in multiple cancer types. Dysfunction in the cell cycle control pathway (TP53, RB1, CCND1, CDKN2A and CCNE1) was dominant, followed by PI3K/AKT cascade (PIK3CA, AKT3, MTOR, TSC1 and TSC2), while genes of WNT signaling pathway (CTNNB1, APC and AXIN2) were mutated at a lower frequency. In addition, 69 variants in 25 DNA damage repair (DDR) genes were identified in 37 (45.7%) patients. Patients with DDR mutations had a higher tumor mutation burden (TMB) than those without DDR mutations. Conclusions: This study revealed a unique genomic landscape of HBV-related HCC. Besides TP53 being the highest mutated gene, a significant fraction of patients was identified with TERT promoter mutations, suggesting that TERT may play a role in HBV-related hepatocarcinogenesis as a novel molecular marker. Furthermore, the most common biological processes affected by HBV status in HCC were cell cycle control, PI3K/AKT and WNT signaling pathways. The possible synergistic effects of HBV in hepatocarcinogenesis warrant further investigations.

scholarly journals Cardiomyocyte cell cycle control and growth estimation in vivo—an analysis based on cardiomyocyte nuclei

2010 ◽  
Vol 86 (3) ◽  
pp. 365-373 ◽  
Author(s):  
Stuart Walsh ◽  
Annica Pontén ◽  
Bernd K. Fleischmann ◽  
Stefan Jovinge
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Control ◽  
Growth Estimation

scholarly journals Overexpression of Bcl-w in the Testis Disrupts Spermatogenesis: Revelation of a Role of BCL-W in Male Germ Cell Cycle Control

2003 ◽  
Vol 17 (9) ◽  
pp. 1868-1879 ◽  
Author(s):  
Wei Yan ◽  
Jun-Xing Huang ◽  
Anna-Stina Lax ◽  
Lauri Pelliniemi ◽  
Eeva Salminen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Germ Cell ◽  
Sertoli Cell ◽  
Germ Cells ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Testicular Development ◽  
Dna Ladder

Abstract To explore physiological roles of BCL-W, a prosurvival member of the BCL-2 protein family, we generated transgenic (TG) mice overexpressing Bcl-w driven by a chicken β-actin promoter. Male Bcl-w TG mice developed normally but were infertile. The adult TG testes displayed disrupted spermatogenesis with various severities ranging from thin seminiferous epithelium containing less germ cells to Sertoli cell-only appearance. No overpopulation of any type of germ cells was observed during testicular development. In contrast, the developing TG testes displayed decreased number of spermatogonia, degeneration, and detachment of spermatocytes and Sertoli cell vacuolization. The proliferative activity of germ cells was significantly reduced during testicular development and spermatogenesis, as determined by in vivo and in vitro 5′-bromo-2′deoxyuridine incorporation assays. Sertoli cells were structurally and functionally normal. The degenerating germ cells were TUNEL-negative and no typical apoptotic DNA ladder was detected. Our data suggest that regulated spatial and temporal expression of BCL-W is required for normal testicular development and spermatogenesis, and overexpression of BCL-W inhibits germ cell cycle entry and/or cell cycle progression leading to disrupted spermatogenesis.

scholarly journals Interchangeable Roles for E2F Transcriptional Repression by the Retinoblastoma Protein and p27KIP1–Cyclin-Dependent Kinase Regulation in Cell Cycle Control and Tumor Suppression

2016 ◽  
Vol 37 (2) ◽  
Author(s):  
Michael J. Thwaites ◽  
Matthew J. Cecchini ◽  
Daniel T. Passos ◽  
Ian Welch ◽  
Frederick A. Dick
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Transcriptional Repression ◽  
Cell Cycle Control ◽  
Retinoblastoma Protein ◽  
Level Control ◽  
Mutant Genotype ◽  
Single Mutant ◽  
Cdk Regulation

ABSTRACT The mammalian G1-S phase transition is controlled by the opposing forces of cyclin-dependent kinases (CDK) and the retinoblastoma protein (pRB). Here, we present evidence for systems-level control of cell cycle arrest by pRB-E2F and p27-CDK regulation. By introducing a point mutant allele of pRB that is defective for E2F repression (Rb1 G ) into a p27KIP1 null background (Cdkn1b −/−), both E2F transcriptional repression and CDK regulation are compromised. These double-mutant Rb1 G/G ; Cdkn1b −/− mice are viable and phenocopy Rb1 +/− mice in developing pituitary adenocarcinomas, even though neither single mutant strain is cancer prone. Combined loss of pRB-E2F transcriptional regulation and p27KIP1 leads to defective proliferative control in response to various types of DNA damage. In addition, Rb1 G/G ; Cdkn1b −/− fibroblasts immortalize faster in culture and more frequently than either single mutant genotype. Importantly, the synthetic DNA damage arrest defect caused by Rb1 G/G ; Cdkn1b −/− mutations is evident in the developing intermediate pituitary lobe where tumors ultimately arise. Our work identifies a unique relationship between pRB-E2F and p27-CDK control and offers in vivo evidence that pRB is capable of cell cycle control through E2F-independent effects.

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