scholarly journals Mechanosensitive expression of lamellipodin promotes intracellular stiffness, cyclin expression, and cell proliferation

2021 ◽  
Author(s):  
Joseph A. Brazzo III ◽  
John C. Biber ◽  
Erik Nimmer ◽  
Yuna Heo ◽  
Linxuan Ying ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Cell Cycle Control ◽  
Cellular Responses ◽  
Good Evidence ◽  
Cycle Progression ◽  
Biophysical Cues

Cell cycle control is a key aspect of numerous physiological and pathological processes. The contribution of biophysical cues, such as stiffness or elasticity of the underlying extracellular matrix (ECM), is critically important in regulating cell cycle progression and proliferation. Indeed, increased ECM stiffness causes aberrant cell cycle progression and proliferation. However, the molecular mechanisms that control these stiffness-mediated cellular responses remain unclear. Here, we address this gap and show good evidence that lamellipodin, previously known as a critical regulator of cell migration, stimulates ECM stiffness-mediated cyclin expression and intracellular stiffening. We observed that increased ECM stiffness upregulates lamellipodin expression. This is mediated by an integrin-dependent FAK-Cas-Rac signaling module and supports stiffness-mediated lamellipodin induction. Mechanistically, we find that lamellipodin overexpression increased and lamellipodin knockdown reduced stiffness-induced cell cyclin expression and cell proliferation, and intracellular stiffness. Overall, these results suggest that lamellipodin levels may be critical for regulating cell proliferation.

scholarly journals LMNB2 promotes the progression of colorectal cancer by silencing p21 expression

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.

scholarly journals Mechanosensitive Expression of Lamellipodin Governs Cell Cycle Progression and Intracellular Stiffness

2020 ◽  
Author(s):  
Joseph A. Brazzo ◽  
Kwonmoo Lee ◽  
Yongho Bae
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Migration ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Cycle Progression ◽  
Cellular Processes ◽  
M Phase ◽  
And Migration ◽  
In Cells

SUMMARYCells exhibit pathological behaviors in response to increased extracellular matrix (ECM) stiffness, including accelerated cell proliferation and migration [1–9], which are correlated with increased intracellular stiffness and tension [2, 3, 10–12]. The biomechanical signal transduction of ECM stiffness into relevant molecular signals and resultant cellular processes is mediated through multiple proteins associated with the actin cytoskeleton in lamellipodia [2, 3, 10, 11, 13]. However, the molecular mechanisms by which lamellipodial dynamics regulate cellular responses to ECM stiffening remain unclear. Previous work described that lamellipodin, a phosphoinositide- and actin filament-binding protein that is known mostly for controlling cell migration [14–21], promotes ECM stiffness-mediated early cell cycle progression [2], revealing a potential commonality between the mechanisms controlling stiffness-dependent cell migration and those controlling cell proliferation. However, i) whether and how ECM stiffness affects the levels of lamellipodin expression and ii) whether stiffness-mediated lamellipodin expression is required throughout cell cycle progression and for intracellular stiffness have not been explored. Here, we show that the levels of lamellipodin expression in cells are significantly increased by a stiff ECM and that this stiffness-mediated lamellipodin upregulation persistently stimulates cell cycle progression and intracellular stiffness throughout the cell cycle, from the early G1 phase to M phase. Finally, we show that both Rac activation and intracellular stiffening are required for the mechanosensitive induction of lamellipodin. More specifically, inhibiting Rac1 activation in cells on stiff ECM reduces the levels of lamellipodin expression, and this effect is reversed by the overexpression of activated Rac1 in cells on soft ECM. We thus propose that lamellipodin is a critical molecular lynchpin in the control of mechanosensitive cell cycle progression and intracellular stiffness.

Integrins and cell proliferation

2001 ◽  
Vol 114 (14) ◽  
pp. 2553-2560 ◽  
Author(s):  
Martin Alexander Schwartz ◽  
Richard K. Assoian
Keyword(s):  
Cell Cycle ◽  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Integrated Control ◽  
G1 Phase ◽  
Erk Pathway ◽  
Cycle Progression ◽  
Cyclin Dependent Kinases

Cell cycle progression in mammalian cells is strictly regulated by both integrin-mediated adhesion to the extracellular matrix and by binding of growth factors to their receptors. This regulation is mediated by G1 phase cyclin-dependent kinases (CDKs), which are downstream of signaling pathways under the integrated control of both integrins and growth factor receptors. Recent advances demonstrate a surprisingly diverse array of integrin-dependent signals that are channeled into the regulation of the G1 phase CDKs. Regulation of cyclin D1 by the ERK pathway may provide a paradigm for understanding how cell adhesion can determine cell cycle progression.

scholarly journals Alternative splicing regulation of cell cycle genes by SPF45/SR140/CHERP complex controls cell proliferation

RNA ◽  
2021 ◽  
pp. rna.078935.121
Author(s):  
Elena Martin ◽  
Claudia Vivori ◽  
Malgorzata Rogalska ◽  
Jorge Herrero ◽  
Juan Valcarcel
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Alternative Splicing ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Splicing Factors ◽  
Splicing Regulation ◽  
Cancer Cell Proliferation ◽  
Cycle Progression ◽  
Regulation Of Cell Cycle

The regulation of pre-mRNA processing has important consequences for cell division and the control of cancer cell proliferation but the underlying molecular mechanisms remain poorly understood. We report that three splicing factors, SPF45, SR140 and CHERP form a tight physical and functionally coherent complex that regulates a variety of alternative splicing events, frequently by repressing short exons flanked by suboptimal 3' splice sites. These comprise alternative exons embedded in genes with important functions in cell cycle progression, including the G2/M key regulator FOXM1 and the spindle regulator SPDL1. Knockdown of either of the three factors leads to G2/M arrest and to enhanced apoptosis in HeLa cells. Promoting the changes in FOXM1 or SPDL1 splicing induced by SPF45/SR140/CHERP knockdown partially recapitulate the effects on cell growth, arguing that the complex orchestrates a program of alternative splicing necessary for efficient cell proliferation.

scholarly journals Human cells lacking CDC14A and CDC14B show differences in ciliogenesis but not in mitotic progression

2020 ◽  
pp. jcs.255950
Author(s):  
Patrick Partscht ◽  
Borhan Uddin ◽  
Elmar Schiebel
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Mitotic Exit ◽  
Human Cells ◽  
Mitotic Progression ◽  
Cycle Progression ◽  
Double Deletion ◽  
Redundant Functions

Budding yeast Cdc14 phosphatase has a central role in mitotic exit and cytokinesis. Puzzlingly, a uniform picture for the three human CDC14 paralogues hCDC14A, B and C in cell cycle control has not emerged to date. Redundant functions between the three hCDC14 phosphatases could explain this unclear picture. To address the possibility of redundancy, we tested expression of hCDC14 and analysed cell cycle progression of cells with single- and double-deletion in hCDC14 genes. Our data suggest that hCDC14C is not expressed in human RPE1 cells excluding a function in this cell line. Single- and double-knockouts (KO) of hCDC14A and hCDC14B in RPE1 cells indicate that both phosphatases are not important for the timing of mitotic phases, cytokinesis and cell proliferation. However, cycling hCDC14A KO and hCDC14B KO cells show altered ciliogenesis compared to WT cells. The cilia of cycling hCDC14A KO cells are longer, whereas hCDC14B KO cilia are more frequent and disassemble faster. In conclusion, this study demonstrates that the cell cycle functions of CDC14 proteins are not conserved between yeast and human cells.

scholarly journals Extracellular Matrix Collagen Alters Cell Proliferation and Cell Cycle Progression of Human Uterine Leiomyoma Smooth Muscle Cells

PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
pp. e75844 ◽  
Author(s):  
Faezeh Koohestani ◽  
Andrea G. Braundmeier ◽  
Arash Mahdian ◽  
Jane Seo ◽  
JiaJia Bi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Uterine Leiomyoma ◽  
Cell Cycle Progression ◽  
Muscle Cells ◽  
Cycle Progression

scholarly journals Cross Interaction between M2 Muscarinic Receptor and Notch1/EGFR Pathway in Human Glioblastoma Cancer Stem Cells: Effects on Cell Cycle Progression and Survival

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 657 ◽  
Author(s):  
Ilaria Cristofaro ◽  
Francesco Alessandrini ◽  
Zaira Spinello ◽  
Claudia Guerriero ◽  
Mario Fiore ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Malignant Gliomas ◽  
Cellular Heterogeneity ◽  
Cycle Progression ◽  
Egfr Expression ◽  
M2 Muscarinic Receptor

Glioblastomas (GBM) are the most aggressive form of primary brain tumors in humans. A key feature of malignant gliomas is their cellular heterogeneity. In particular, the presence of an undifferentiated cell population of defined Glioblastoma Stem cells (GSCs) was reported. Increased expression of anti-apoptotic and chemo-resistance genes in GCSs subpopulation favors their high resistance to a broad spectrum of drugs. Our previous studies showed the ability of M2 muscarinic receptors to negatively modulate the cell growth in GBM cell lines and in the GSCs. The aim of this study was to better characterize the inhibitory effects of M2 receptors on cell proliferation and survival in GSCs and investigate the molecular mechanisms underlying the M2-mediated cell proliferation arrest and decreased survival. Moreover, we also evaluated the ability of M2 receptors to interfere with Notch1 and EGFR pathways, whose activation promotes GSCs proliferation. Our data demonstrate that M2 receptors activation impairs cell cycle progression and survival in the primary GSC lines analyzed (GB7 and GB8). Moreover, we also demonstrated the ability of M2 receptor to inhibit Notch1 and EGFR expression, highlighting a molecular interaction between M2 receptor and the Notch-1/EGFR pathways also in GSCs.

scholarly journals Potassium channels in cell cycle and cell proliferation

2014 ◽  
Vol 369 (1638) ◽  
pp. 20130094 ◽  
Author(s):  
Diana Urrego ◽  
Adam P. Tomczak ◽  
Farrah Zahed ◽  
Walter Stühmer ◽  
Luis A. Pardo
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Potassium Channels ◽  
Normal Cell ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Control Mechanisms ◽  
Cycle Progression ◽  
Uncontrolled Cell Proliferation ◽  
Normal Cell Cycle

Normal cell-cycle progression is a crucial task for every multicellular organism, as it determines body size and shape, tissue renewal and senescence, and is also crucial for reproduction. On the other hand, dysregulation of the cell-cycle progression leading to uncontrolled cell proliferation is the hallmark of cancer. Therefore, it is not surprising that it is a tightly regulated process, with multifaceted and very complex control mechanisms. It is now well established that one of those mechanisms relies on ion channels, and in many cases specifically on potassium channels. Here, we summarize the possible mechanisms underlying the importance of potassium channels in cell-cycle control and briefly review some of the identified channels that illustrate the multiple ways in which this group of proteins can influence cell proliferation and modulate cell-cycle progression.

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

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.

scholarly journals The balance between cell cycle arrest and cell proliferation: control by the extracellular matrix and by contact inhibition

2014 ◽  
Vol 4 (3) ◽  
pp. 20130075 ◽  
Author(s):  
Claude Gérard ◽  
Albert Goldbeter
Keyword(s):  
Cell Cycle ◽  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Cell Density ◽  
Cell Cycle Progression ◽  
Contact Inhibition ◽  
Critical Threshold ◽  
Cycle Progression ◽  
Cycle Arrest

To understand the dynamics of the cell cycle, we need to characterize the balance between cell cycle arrest and cell proliferation, which is often deregulated in cancers. We address this issue by means of a detailed computational model for the network of cyclin-dependent kinases (Cdks) driving the mammalian cell cycle. Previous analysis of the model focused on how this balance is controlled by growth factors (GFs) or the levels of activators (oncogenes) and inhibitors (tumour suppressors) of cell cycle progression. Supra-threshold changes in the level of any of these factors can trigger a switch in the dynamical behaviour of the Cdk network corresponding to a bifurcation between a stable steady state, associated with cell cycle arrest, and sustained oscillations of the various cyclin/Cdk complexes, corresponding to cell proliferation. Here, we focus on the regulation of cell proliferation by cellular environmental factors external to the Cdk network, such as the extracellular matrix (ECM), and contact inhibition, which increases with cell density. We extend the model for the Cdk network by including the phenomenological effect of both the ECM, which controls the activation of the focal adhesion kinase (FAK) that promotes cell cycle progression, and cell density, which inhibits cell proliferation via the Hippo/YAP pathway. The model shows that GFs and FAK activation are capable of triggering in a similar dynamical manner the transition to cell proliferation, while the Hippo/YAP pathway can arrest proliferation once cell density passes a critical threshold. The results account for the dependence or independence of cell proliferation on serum and/or cell anchorage to ECM. Whether the balance in the Cdk network is tilted towards cell cycle arrest or proliferation depends on the direction in which the threshold associated with the bifurcation is passed once the cell integrates the multiple, internal or external signals that promote or impede progression in the cell cycle.

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