Lysophosphatidic Acid Mediates Imiquimod-Induced Psoriasis-like Symptoms by Promoting Keratinocyte Proliferation through LPAR1/ROCK2/PI3K/AKT Signaling Pathway

Psoriasis is a chronic inflammatory skin disease. Recently, lysophosphatidic acid (LPA)/LPAR5 signaling has been reported to be involved in both NLRP3 inflammasome activation in macrophages and keratinocyte activation to produce inflammatory cytokines, contributing to psoriasis pathogenesis. However, the effect and molecular mechanisms of LPA/LPAR signaling in keratinocyte proliferation in psoriasis remain unclear. In this study, we investigated the effects of LPAR1/3 inhibition on imiquimod (IMQ)-induced psoriasis-like mice. Treatment with the LPAR1/3 antagonist, ki16425, alleviated skin symptoms in IMQ-induced psoriasis-like mouse models and decreased keratinocyte proliferation in the lesion. It also decreased LPA-induced cell proliferation and cell cycle progression via increased cyclin A2, cyclin D1, cyclin-dependent kinase (CDK)2, and CDK4 expression and decreased p27Kip1 expression in HaCaT cells. LPAR1 knockdown in HaCaT cells reduced LPA-induced proliferation, suppressed cyclin A2 and CDK2 expression, and restored p27Kip1 expression. LPA increased Rho-associated protein kinase 2 (ROCK2) expression and PI3K/AKT activation; moreover, the pharmacological inhibition of ROCK2 and PI3K/AKT signaling suppressed LPA-induced cell cycle progression. In conclusion, we demonstrated that LPAR1/3 antagonist alleviates IMQ-induced psoriasis-like symptoms in mice, and in particular, LPAR1 signaling is involved in cell cycle progression via ROCK2/PI3K/AKT pathways in keratinocytes.

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Insulin-like Growth Factor-I Extendsin VitroReplicative Life Span of Skeletal Muscle Satellite Cells by Enhancing G1/S Cell Cycle Progression via the Activation of Phosphatidylinositol 3′-Kinase/Akt Signaling Pathway

Journal of Biological Chemistry ◽

10.1074/jbc.m005832200 ◽

2000 ◽

Vol 275 (46) ◽

pp. 35942-35952 ◽

Cited By ~ 154

Author(s):

Manu V. Chakravarthy ◽

Tsghe W. Abraha ◽

Robert J. Schwartz ◽

Marta L. Fiorotto ◽

Frank W. Booth

Keyword(s):

Cell Cycle ◽

Skeletal Muscle ◽

Growth Factor ◽

Satellite Cells ◽

Cell Cycle Progression ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Phosphatidylinositol 3 Kinase ◽

Cycle Progression ◽

Factor I

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Suppression of cell cycle progression by Jun dimerization protein (JDP2) involves down-regulation of cyclin A2

Nature Precedings ◽

10.1038/npre.2009.3840.1 ◽

2009 ◽

Author(s):

Jianzhi Pan ◽

Koji Nakade ◽

Satoko Masuzaki ◽

Hitomi Hasegawa ◽

Yu-Chang Huang ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Down Regulation ◽

Cycle Progression ◽

Cyclin A2

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PI3K/Akt/FOXO3a Pathway Contributes to Thrombopoietin-Induced Proliferation of Primary Megakaryocytes In Vitro and In Vivo Via Modulation of p27Kip1.

Blood ◽

10.1182/blood.v106.11.202.202 ◽

2005 ◽

Vol 106 (11) ◽

pp. 202-202

Author(s):

Takafumi Nakao ◽

Amy E Geddis ◽

Norma E. Fox ◽

Kenneth Kaushansky

Keyword(s):

Cell Cycle ◽

Cell Line ◽

Cell Cycle Progression ◽

Wild Type ◽

Cycle Progression ◽

P27kip1 Expression ◽

Cell Counts ◽

Deficient Mice

Abstract Thrombopoietin (TPO), the primary regulator of megakaryocyte (MK) and platelet formation, modulates the activity of multiple signal transduction molecules, including those in the Jak/STAT, p42/p44 MAPK, and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. In the previous study, we reported that PI3K and Akt are necessary for TPO-induced cell cycle progression of primary MK progenitors. The absence of PI3K activity results in a block of transition from G1 to S phase in these cells (Geddis AE et al. JBC2001276:34473–34479). However, the molecular events secondary to the activation of PI3K/Akt responsible for MK proliferation remain unclear. In this study we show that FOXO3a and its downstream target p27Kip1 play an important role in TPO-induced proliferation of MK progenitors. TPO induces phosphorylation of Akt and FOXO3a in both UT-7/TPO, a megakaryocytic cell line, and primary murine MKs in a PI3K dependent fashion. Cell cycle progression of UT-7/TPO cells is blocked in G1 phase by inhibition of PI3K. We found that TPO down-modulates p27Kip1 expression at both the mRNA and protein levels in UT-7/TPO cells and primary MKs in a PI3K dependent fashion. UT-7/TPO stably expressing constitutively active Akt or a dominant-negative form of FOXO3a failed to induce p27Kip1 expression after TPO withdrawal. Induced expression of an active form of FOXO3a resulted in increased p27Kip1 expression in this cell line. In an attempt to assess whether FOXO3a has an effect of MK proliferation in vivo, we compared the number of MKs in Foxo3a-deficient mice and in wild type controls. Although peripheral blood cell counts of erythrocytes, neutrophils, monocytes and platelets were normal in the Foxo3a-deficient mice, total nucleated marrow cell count of Foxo3a-deficient mice were 60% increased compared with wild type controls. In addition, the increase of MKs was more profound than that of total nucleated marrow cells; CD41+ MKs from Foxo3a-deficient mice increased 2.1-fold, and mature MKs with 8N and greater ploidy increased 2.5-fold, compared with wild type controls. Taken together with the previous observation that p27Kip1-deficient mice also display increased numbers of MK progenitors, our findings strongly suggest that the effect of TPO on MK proliferation is mediated by PI3K/Akt-induced FOXO3a inactivation and subsequent p27Kip1 down-regulation in vitro and in vivo.

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Impact of aryl hydrocarbon receptor (AhR) knockdown on cell cycle progression in human HaCaT keratinocytes

Biological Chemistry ◽

10.1515/bc.2011.067 ◽

2011 ◽

Vol 392 (7) ◽

Cited By ~ 27

Author(s):

Michaela Kalmes ◽

Jenny Hennen ◽

Judith Clemens ◽

Brunhilde Blömeke

Keyword(s):

Cell Cycle ◽

Aryl Hydrocarbon Receptor ◽

Protein Level ◽

Cell Cycle Progression ◽

Physiological Function ◽

Hacat Cells ◽

Cyclin Dependent Kinase ◽

Cycle Progression ◽

Aryl Hydrocarbon ◽

Exogenous Ligands

Abstract While activation of the aryl hydrocarbon receptor (AhR) by exogenous ligands is well investigated, its physiological function is less understood. By extending research in AhR biology, evidence appeared that the receptor generally plays an important role in cell physiology. In keratinocytes, little is known about endogenous functions of the AhR. In order to expand this knowledge, we analyzed the impact of AhR knockdown on cell cycle progression in HaCaT cells and showed that proliferation of siAhR HaCaT cells was significantly decreased. In line with that result, western blot analysis revealed that protein level of the cyclin dependent kinase inhibitor p27KIP1 was increased, whereas protein level of the cyclin dependent kinase (CDK) 2 was reduced. CDK4 and CDK6 protein levels remained unchanged, whereas protein level of the retinoblastoma protein (pRB) was reduced. By measuring ethoxyresorufin-O-deethylase (EROD) activity we showed that endogenous cytochrome P450 1 (CYP1), especially CYP1A1 is required for normal cell cycle in HaCaT cells, as well. To the best of our knowledge, we provide evidence for the first time in human skin cells, that in the absence of exogenous ligands, the AhR promotes cell cycle progression in HaCaT cells and one can speculate that this is the physiological function of this receptor in keratinocytes.

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TRPC1 promotes the genesis and progression of colorectal cancer via activating CaM-mediated PI3K/AKT signaling axis

Oncogenesis ◽

10.1038/s41389-021-00356-5 ◽

2021 ◽

Vol 10 (10) ◽

Author(s):

Yang Sun ◽

Chen Ye ◽

Wen Tian ◽

Wen Ye ◽

Yuan-Yuan Gao ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Cycle ◽

Tumor Growth ◽

Cell Cycle Progression ◽

Akt Signaling ◽

Cycle Progression ◽

Colorectal Tumorigenesis ◽

Signaling Axis

AbstractTransient receptor potential canonical (TRPC) channels are the most prominent nonselective cation channels involved in various diseases. However, the function, clinical significance, and molecular mechanism of TRPCs in colorectal cancer (CRC) progression remain unclear. In this study, we identified that TRPC1 was the major variant gene of the TRPC family in CRC patients. TRPC1 was upregulated in CRC tissues compared with adjacent normal tissues and high expression of TRPC1 was associated with more aggressive tumor progression and poor overall survival. TRPC1 knockdown inhibited cell proliferation, cell-cycle progression, invasion, and migration in vitro, as well as tumor growth in vivo; whereas TRPC1 overexpression promoted colorectal tumor growth and metastasis in vitro and in vivo. In addition, colorectal tumorigenesis was significantly attenuated in Trpc1-/- mice. Mechanistically, TRPC1 could enhance the interaction between calmodulin (CaM) and the PI3K p85 subunit by directly binding to CaM, which further activated the PI3K/AKT and its downstream signaling molecules implicated in cell cycle progression and epithelial-mesenchymal transition. Silencing of CaM attenuated the oncogenic effects of TRPC1. Taken together, these results provide evidence that TRPC1 plays a pivotal oncogenic role in colorectal tumorigenesis and tumor progression by activating CaM-mediated PI3K/AKT signaling axis. Targeting TRPC1 represents a novel and specific approach for CRC treatment.

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Erratum: Suppression of cell-cycle progression by Jun dimerization protein-2 (JDP2) involves downregulation of cyclin-A2

Oncogene ◽

10.1038/onc.2011.285 ◽

2011 ◽

Vol 30 (33) ◽

pp. 3648-3648

Author(s):

J Pan ◽

K Nakade ◽

Y-C Huang ◽

Z-W Zhu ◽

S Masuzaki ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Cyclin A2

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Vav1 Promotes T Cell Cycle Progression by Linking TCR/CD28 Costimulation to FOXO1 and p27kip1 Expression

The Journal of Immunology ◽

10.4049/jimmunol.177.8.5024 ◽

2006 ◽

Vol 177 (8) ◽

pp. 5024-5031 ◽

Cited By ~ 41

Author(s):

Céline Charvet ◽

Ann Janette Canonigo ◽

Stéphane Bécart ◽

Ulrich Maurer ◽

Ana V. Miletic ◽

...

Keyword(s):

Cell Cycle ◽

T Cell ◽

Cell Cycle Progression ◽

Cycle Progression ◽

P27kip1 Expression ◽

Cd28 Costimulation

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Cyclin A2: a genuine cell cycle regulator?

BioMolecular Concepts ◽

10.1515/bmc-2012-0027 ◽

2012 ◽

Vol 3 (6) ◽

pp. 535-543 ◽

Cited By ~ 11

Author(s):

Nawal Bendris ◽

Abdelhalim Loukil ◽

Caroline Cheung ◽

Nikola Arsic ◽

Cosette Rebouissou ◽

...

Keyword(s):

Cell Cycle ◽

Posttranslational Modifications ◽

Cell Cycle Progression ◽

Current Knowledge ◽

Cell Cycle Regulators ◽

Cycle Progression ◽

Cell Cycle Regulator ◽

Its Gene ◽

Cyclin A2 ◽

Shed Light

AbstractCyclin A2 belongs to the core cell cycle regulators and participates in the control of both S phase and mitosis. However, several observations suggest that it is also endowed with other functions, and our recent data shed light on its involvement in cytoskeleton dynamic and cell motility. From the transcription of its gene to its posttranslational modifications, cyclin A2 regulation reveals the complexity of the regulatory network shaping cell cycle progression. We summarize our current knowledge on this cell cycle regulator and discuss recent findings raising the possibility that cyclin A2 might play a much broader role in epithelial tissues homeostasis.

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