Mathematical modeling reveals a critical role for cyclin D1 dynamics in phenotype switching during glioma differentiation

Pulmonary artery remodelling is a key feature in the pathological progress of pulmonary arterial hypertension (PAH). Moreover, excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) plays a critical role in the pathogenesis of pulmonary artery remodelling. Neuroblastoma suppressor of tumorigenicity 1 (NBL1) has been previously shown to induce growth inhibition in tumour cells. However, the effect of NBL1 in the regulation of human PASMC proliferation remains unclear. In cultured human PASMCs, we observed a dose-dependent inhibitory effect of NBL1 on platelet derived growth factor (PDGF)-BB-induced cell growth, DNA synthesis and proliferating cell nuclear antigen (PCNA) expression, as measured by MTS assay, 5-ethynil-2-deoxyuridine (EdU) analysis and western blots respectively. We also detected the expression and activities of cell-cycle positive regulators (cyclin D1, cyclin E, CDK2, CDK4 and CDK6) and negative regulators (p21 and p27) in human PASMCs by western blots and co-immuoprecipitation (IP). Our results show that NBL1-induced growth suppression is associated with the decreased activity of cyclin D1–CDK4 and the decreased phosphorylation of p27 in PDGF-BB-treated human PASMCs. By western blots using the phosphor-specific antibodies, we further demonstrated that NBL1 induced growth suppression is mediated by blockade of the up-stream PDGF-receptor β (PDGFRβ)-p38 mitogen-activated protein kinase (MAPK). In conclusion, our results suggest that NBL1 could inhibit PDGF-BB-induced human PASMC proliferation, and the underlying mechanism is associated with the decreased cyclin D1–CDK4 activity and up-regulated p27 by decreasing the phosphorylation of p27 via blockade of PDGFRβ-p38MAPK signal cascade. Our findings may provide a potential therapeutic target for PAH.

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Critical Role of Cyclin D1 Nuclear Import in Cardiomyocyte Proliferation

Circulation Research ◽

10.1161/01.res.0000049105.15329.1c ◽

2003 ◽

Vol 92 (1) ◽

Cited By ~ 91

Author(s):

Mimi Tamamori-Adachi ◽

Hiroshi Ito ◽

Piyamas Sumrejkanchanakij ◽

Susumu Adachi ◽

Michiaki Hiroe ◽

...

Keyword(s):

Cyclin D1 ◽

Nuclear Import ◽

Critical Role ◽

Cardiomyocyte Proliferation

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Cdk2 plays a critical role in hepatocyte cell cycle progression and survival in the setting of cyclin D1 expression in vivo

Cell Cycle ◽

10.4161/cc.8.17.9465 ◽

2009 ◽

Vol 8 (17) ◽

pp. 2802-2809 ◽

Cited By ~ 21

Author(s):

Eric A. Hanse ◽

Christopher J. Nelsen ◽

Melissa M. Goggin ◽

Chelsea K. Anttila ◽

Lisa K. Mullany ◽

...

Keyword(s):

Cell Cycle ◽

Cyclin D1 ◽

Cell Cycle Progression ◽

Critical Role ◽

Cycle Progression

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The MNK1/2-eIF4E axis drives melanoma plasticity, progression, and resistance to immunotherapy

10.1101/2020.05.29.117531 ◽

2020 ◽

Author(s):

Fan Huang ◽

Christophe Gonçalves ◽

Margarita Bartish ◽

Joelle Rémy-Sarrazin ◽

Qianyu Guo ◽

...

Keyword(s):

Mouse Model ◽

Critical Role ◽

Inflammatory Factors ◽

Genetic Ablation ◽

Immune Exhaustion ◽

New Strategy ◽

Phenotype Switch ◽

Phenotype Switching ◽

Immunosuppressive Microenvironment

AbstractMelanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Melanoma plasticity exhibited as phenotype switching contributes to immunotherapy resistance, however the mechanisms are not completely understood and thus therapeutically unexploited. Here, using a transgenic melanoma mouse model, we demonstrated a critical role of the MNK1/2-eIF4E axis in melanoma plasticity and resistance to immunotherapy. We showed that phospho-eIF4E deficient murine melanomas express high levels of melanocytic antigens, with similar results verified in patient melanomas. Mechanistically, we identified that phospho-eIF4E controls the translation of NGFR, a critical effector of phenotype switching. In patients with melanoma, the expression of MKNK1, the kinase for eIF4E, positively correlated with markers of immune exhaustion. Genetic ablation of phospho-eIF4E reprogrammed the immunosuppressive microenvironment, exemplified by lowered production of inflammatory factors and increased CD8+ T cell infiltrates. Blocking phospho-eIF4E, using MNK1/2 inhibitors, offers a new strategy to inhibit melanoma plasticity and improve the survival response to anti-PD-1 immunotherapy.

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Differentiation of C2C12 myoblasts is critically regulated by FAK signaling

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00348.2004 ◽

2005 ◽

Vol 289 (3) ◽

pp. R862-R870 ◽

Cited By ~ 48

Author(s):

Carolina F. M. Z. Clemente ◽

Marcus A. F. Corat ◽

Sara T. O. Saad ◽

Kleber G. Franchini

Keyword(s):

Cyclin D1 ◽

Culture Medium ◽

Critical Role ◽

Terminal Differentiation ◽

Wild Type ◽

Proliferating Cells ◽

C2c12 Myoblasts ◽

Differentiation Medium ◽

Preferential Location ◽

Autophosphorylation Site

This study examined whether focal adhesion kinase (FAK) plays a role in the differentiation of C2C12 myoblasts into myotubes. Differentiation of C2C12 myoblasts induced by switch to differentiation culture medium was accompanied by a transient reduction of FAK phosphorylation at Tyr-397 (to ∼50%, at 1 and 2 h), followed by an increase thereafter (to 240% up to 5 days), although FAK protein expression remained unchanged. FAK and phosphorylated FAK were found at the edge of lamellipodia in proliferating cells, whereas the later increase in FAK phosphorylation in differentiating cells was accompanied by its preferential location at the tip of well-organized actin stress fibers. Hyperexpression of FAK autophosphorylation site (Tyr-397) mutant (MT-FAK) reduced FAK phosphorylation at Tyr-397 in proliferating cells and was accompanied by reduction of cyclin D1 and increase of myogenin expression. These cells failed to progress to myotubes in differentiation medium. In contrast, hyperexpression of a wild-type FAK construction (WT-FAK) increased baseline and abolished the transient reduction of FAK phosphorylation at Tyr-397 in serum-starved C2C12 cells. Cells transfected with WT-FAK failed to reduce cyclin D1 and to increase myogenin expression, as well as to progress to terminal differentiation in differentiation medium. These data indicate that FAK signaling plays a critical role in the control of cell cycle as well as in the progression of C2C12 cells to terminal differentiation. Transient inhibition of FAK phosphorylation at Tyr-397 contributes to trigger the myogenic genetic program, but its later activation is also central to terminal differentiation into myotubes.

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Upregulation of miR-124-3p by Liver X Receptor Inhibits the Growth of Hepatocellular Carcinoma Cells Via Suppressing Cyclin D1 and CDK6

Technology in Cancer Research & Treatment ◽

10.1177/1533033820967473 ◽

2020 ◽

Vol 19 ◽

pp. 153303382096747

Author(s):

Dan Zhong ◽

Xilin Lyu ◽

Xiaohong Fu ◽

Peng Xie ◽

Menggang Liu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Growth ◽

Cyclin D1 ◽

Therapeutic Target ◽

Target Genes ◽

Critical Role ◽

Liver X Receptor ◽

Potential Therapeutic Target ◽

Hcc Cells

MiR-124-3p has been identified as a novel tumor suppressor and a potential therapeutic target in hepatocellular carcinoma (HCC) through regulating its target genes. However, the upstream regulatory mechanisms of mir-124-3p in HCC has not been fully understood. The transcription factor liver X receptor (LXR) plays a critical role in suppressing the proliferation of HCC cells, but it is unclear whether LXR is involved in the regulation of mir-124-3p. In the present study, we demonstrated that the expression of mir-124-3p was positively correlated with that of LXR in HCC, and the cell growth of HCC was significantly inhibited by LXR agonists. Moreover, activation of LXR with the agonists up-regulated the expression of mir-124-3p, and in turn down-regulated cyclin D1 and cyclin-dependent kinase 6 (CDK6) expression, which are the target genes of mir-124-3p. Mechanistically, miR-124-3p mediates LXR induced inhibition of HCC cell growth and down-regulation of cyclin D1 and CDK6 expression. In vivo experiments also confirmed that LXR induced miR-124-3p expression inhibited the growth of HCC xenograft tumors, as well as cyclin D1 and CDK6 expression. Our findings revealed that miR-124-3p is a novel target gene of LXR, and regulation of the miR-124-3p-cyclin D1/CDK6 pathway by LXR plays a crucial role in the proliferation of HCC cells. LXR-miR-124-3p-cyclin D1/CDK6 pathway may be a novel potential therapeutic target for HCC treatment.

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Sequestration of p27Kip1 protein by cyclin D1 in typical and blastic variants of mantle cell lymphoma (MCL): implications for pathogenesis

Blood ◽

10.1182/blood-2002-01-0263 ◽

2003 ◽

Vol 101 (8) ◽

pp. 3181-3187 ◽

Cited By ~ 56

Author(s):

Leticia Quintanilla-Martinez ◽

Theresa Davies-Hill ◽

Falko Fend ◽

Julia Calzada-Wack ◽

Lynn Sorbara ◽

...

Keyword(s):

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lines ◽

Kinase Inhibitor ◽

Cell Lymphoma ◽

Critical Role ◽

Cellular Growth ◽

P27kip1 Protein ◽

Cyclin Dependent Kinase Inhibitor ◽

Mantle Cell

Abstract p27 is a cyclin-dependent kinase inhibitor that plays a critical role in regulating G1/S progression, and whose activity is, in part, regulated through interactions with D-type cyclins. Mantle cell lymphoma (MCL) is characterized by the t(11;14) translocation resulting in deregulated cyclin D1. We previously showed that p27 expression in MCL, as assessed by immunohistochemistry (IHC), does not show the usual inverse relationship to proliferate seen in most other lymphomas that do not overexpress cyclin D1. This suggested that the normal expression or control of p27 activity on cell growth might be altered through potential interactions with cyclin D1. Using Western blot and coimmunoprecipitation studies, we assessed the interrelationship between cyclin D1 and p27 in several cyclin D1+ cell lines and primary MCL cases. Similar to our previous results by IHC, typical MCLs showed lower expression of p27 when compared to the more highly proliferative blastic cases or cell lines (mean arbitrary units: 58 versus 236 versus 120). Cyclin D1 was expressed at variable levels in both typical and blastic MCLs. p27 protein could be consistently coimmunoprecipitated with cyclin D1 from both cell lines and cases. Using techniques of exhaustive immunoprecipitation, we could demonstrate that most p27 protein was sequestered into complexes containing cyclin D1. We hypothesize that mantle cell lymphomagenesis results not only from direct consequences of inappropriate cyclin D1 expression, but also from the ability of overexpressed cyclin D1 to buffer physiologic changes in p27 levels, thereby rendering p27 ineffective as an inhibitor of cellular growth.

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Phosphorylation of Cyclin D1 Regulated by ATM or ATR Controls Cell Cycle Progression

Molecular and Cellular Biology ◽

10.1128/mcb.02047-07 ◽

2008 ◽

Vol 28 (17) ◽

pp. 5478-5493 ◽

Cited By ~ 23

Author(s):

Masahiro Hitomi ◽

Ke Yang ◽

Andrew W. Stacey ◽

Dennis W. Stacey

Keyword(s):

Cell Cycle ◽

Dna Synthesis ◽

Cyclin D1 ◽

Cell Cycle Progression ◽

Critical Role ◽

Cycle Progression ◽

Checkpoint Kinase ◽

Checkpoint Kinases ◽

Stressed Cells ◽

Interfering Rna

ABSTRACT Cyclin D1 is required at high levels for passage through G1 phase but must be reduced to low levels during S phase to avoid the inhibition of DNA synthesis. This suppression requires the phosphorylation of Thr286, which is induced directly by DNA synthesis. Because the checkpoint kinase ATR is activated by normal replication as well as by DNA damage, its potential role in regulating cyclin D1 phosphorylation was tested. We found that ATR, activated by either UV irradiation or the topoisomerase IIβ binding protein 1 activator, promoted cyclin D1 phosphorylation. Small interfering RNA against ATR inhibited UV-induced Thr286 phosphorylation, together with that seen in normally cycling cells, indicating that ATR regulates cyclin D1 phosphorylation in normal as well as stressed cells. Following double-stranded DNA (dsDNA) breakage, the related checkpoint kinase ATM was also able to promote the phosphorylation of cyclin D1 Thr286. The relationship between these checkpoint kinases and cyclin D1 was extended when we found that normal cell cycle blockage in G1 phase observed following dsDNA damage was efficiently overcome when exogenous cyclin D1 was expressed within the cells. These results indicate that checkpoint kinases play a critical role in regulating cell cycle progression in normal and stressed cells by directing the phosphorylation of cyclin D1.

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