p27kip1 controls H-Ras/MAPK activation and cell cycle entry via modulation of MT stability

The cyclin-dependent kinase (CDK) inhibitor p27kip1 is a critical regulator of the G1/S-phase transition of the cell cycle and also regulates microtubule (MT) stability. This latter function is exerted by modulating the activity of stathmin, an MT-destabilizing protein, and by direct binding to MTs. We recently demonstrated that increased proliferation in p27kip1-null mice is reverted by concomitant deletion of stathmin in p27kip1/stathmin double-KO mice, suggesting that a CDK-independent function of p27kip1 contributes to the control of cell proliferation. Whether the regulation of MT stability by p27kip1 impinges on signaling pathway activation and contributes to the decision to enter the cell cycle is largely unknown. Here, we report that faster cell cycle entry of p27kip1-null cells was impaired by the concomitant deletion of stathmin. Using gene expression profiling coupled with bioinformatic analyses, we show that p27kip1 and stathmin conjunctly control activation of the MAPK pathway. From a molecular point of view, we observed that p27kip1, by controlling MT stability, impinges on H-Ras trafficking and ubiquitination levels, eventually restraining its full activation. Our study identifies a regulatory axis controlling the G1/S-phase transition, relying on the regulation of MT stability by p27kip1 and finely controlling the spatiotemporal activation of the Ras-MAPK signaling pathway.

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Involvement of the p38 MAPK signaling pathway in S-phase cell-cycle arrest induced by Furazolidone in human hepatoma G2 cells

Journal of Applied Toxicology ◽

10.1002/jat.2829 ◽

2012 ◽

Vol 33 (12) ◽

pp. 1500-1505 ◽

Cited By ~ 6

Author(s):

Yu Sun ◽

Shusheng Tang ◽

Xi Jin ◽

Chaoming Zhang ◽

Wenxia Zhao ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Signaling Pathway ◽

P38 Mapk ◽

Mapk Signaling ◽

S Phase ◽

Mapk Signaling Pathway ◽

Phase Cell ◽

Human Hepatoma ◽

Cycle Arrest

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Spirulina Crude Protein Promotes the Migration and Proliferation in IEC-6 Cells by Activating EGFR/MAPK Signaling Pathway

Marine Drugs ◽

10.3390/md17040205 ◽

2019 ◽

Vol 17 (4) ◽

pp. 205

Author(s):

Su-Jin Jeong ◽

Jeong-Wook Choi ◽

Min-Kyeong Lee ◽

Youn-Hee Choi ◽

Taek-Jeong Nam

Keyword(s):

Cell Cycle ◽

Epithelial Cells ◽

Signaling Pathway ◽

Crude Protein ◽

Cell Cycle Progression ◽

Intestinal Epithelial Cells ◽

Mapk Signaling ◽

S Phase ◽

Intestinal Epithelial ◽

Cycle Progression

Spirulina is a type of filamentous blue-green microalgae known to be rich in nutrients and to have pharmacological effects, but the effect of spirulina on the small intestine epithelium is not well understood. Therefore, this study aims to investigate the proliferative effects of spirulina crude protein (SPCP) on a rat intestinal epithelial cells IEC-6 to elucidate the mechanisms underlying its effect. First, the results of wound-healing and cell viability assays demonstrated that SPCP promoted migration and proliferation in a dose-dependent manner. Subsequently, when the mechanisms of migration and proliferation promotion by SPCP were confirmed, we found that the epidermal growth factor receptor (EGFR) and mitogen-activated protein (MAPK) signaling pathways were activated by phosphorylation. Cell cycle progression from G0/G1 to S phase was also promoted by SPCP through upregulation of the expression levels of cyclins and cyclin-dependent kinases (Cdks), which regulate cell cycle progression to the S phase. Meanwhile, the expression of cyclin-dependent kinase inhibitors (CKIs), such as p21 and p27, decreased with SPCP. In conclusion, our results indicate that activation of EGFR and its downstream signaling pathway by SPCP treatment regulates cell cycle progression. Therefore, these results contribute to the research on the molecular mechanism for SPCP promoting the migration and proliferation of rat intestinal epithelial cells.

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Mnt–Max to Myc–Max complex switching regulates cell cycle entry

The Journal of Cell Biology ◽

10.1083/jcb.200411013 ◽

2005 ◽

Vol 169 (3) ◽

pp. 405-413 ◽

Cited By ~ 51

Author(s):

William Walker ◽

Zi-Qiang Zhou ◽

Sara Ota ◽

Anthony Wynshaw-Boris ◽

Peter J. Hurlin

Keyword(s):

Phase Transition ◽

Cell Cycle ◽

Cell Proliferation ◽

Mouse Embryo ◽

Target Genes ◽

S Phase ◽

Cell Cycle Entry ◽

Mouse Embryo Fibroblasts ◽

E Box ◽

Important Regulator

The c-Myc oncoprotein is strongly induced during the G0 to S-phase transition and is an important regulator of cell cycle entry. In contrast to c-Myc, the putative Myc antagonist Mnt is maintained at a constant level during cell cycle entry. Mnt and Myc require interaction with Max for specific DNA binding at E-box sites, but have opposing transcriptional activities. Here, we show that c-Myc induction during cell cycle entry leads to a transient decrease in Mnt–Max complexes and a transient switch in the ratio of Mnt–Max to c-Myc–Max on shared target genes. Mnt overexpression suppressed cell cycle entry and cell proliferation, suggesting that the ratio of Mnt–Max to c-Myc–Max is critical for cell cycle entry. Furthermore, simultaneous Cre-Lox mediated deletion of Mnt and c-Myc in mouse embryo fibroblasts rescued the cell cycle entry and proliferative block caused by c-Myc ablation alone. These results demonstrate that Mnt-Myc antagonism plays a fundamental role in regulating cell cycle entry and proliferation.

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Antiprolactinoma Effect of Hordenine by Inhibiting MAPK Signaling Pathway Activation in Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/3107290 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Xiong Wang ◽

Run-zhu Guo ◽

Li Ma ◽

Qiao-yan Ding ◽

Jun-hua Meng ◽

...

Keyword(s):

Pituitary Gland ◽

Signaling Pathway ◽

Mapk Pathway ◽

Interleukin 1 ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Mitogen Activated Protein Kinase ◽

Pathway Activation ◽

Mitogen Activated Protein ◽

Jnk Activation

Prolactinomas are harmful to human health, and the clinical first-line treatment drug is bromocriptine. However, 20% prolactinomas patients did not respond to bromocriptine. Hordenine is an alkaloid separated from Fructus Hordei Germinatus, which showed significant antihyperprolactinemia activity in rats. The aim of this study was to explore the effect and mechanism of hordenine on prolactinomas in rats. The study used estradiol to induce prolactinomas, which caused the activation of the pituitary mitogen-activated protein kinase (MAPK) pathway in rats significantly. The treatment of hordenine restored estradiol, induced the overgrowth of pituitary gland, and reduced the prolactin (PRL) accumulation in the serum and pituitary gland of rats by blocking the MAPK (p38, ERK1/2, and JNK) activation and production of inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). The antiprolactinoma effect of hordenine was mediated by inhibiting the MAPK signaling pathway activation in rats.

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Role of p38 MAPK pathway in apoptosis induction by saturated fatty acid in human pancreatic β-cells

Problems of Endocrinology ◽

10.14341/probl201662513-14 ◽

2016 ◽

Vol 62 (5) ◽

pp. 13-14

Author(s):

Jan Šrámek ◽

Vlasta Němcová-Fürstová ◽

Kamila Balušíková ◽

Petr Daniel ◽

Michael Jelínek ◽

...

Keyword(s):

Signaling Pathway ◽

P38 Mapk ◽

Mapk Pathway ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Erk Pathway ◽

Apoptosis Induction ◽

Β Cells ◽

Pancreatic Β Cells ◽

Pathway Activation

Background. Pancreatic β-cells failure and apoptosis in response to chronically elevated concentrations of saturated fatty acids in blood was considered as one of the main causes of type 2 diabetes mellitus development. Although precise molecular mechanisms of this process are still unclear, there are some indications that the p38 MAPK signaling pathway could be involved.Aim, materials and methods. Therefore, we tested the role of p38 MAPK signaling pathway activation in apoptosis induction by SA in human pancreatic β-cells NES2Y. Crosstalk between p38 MAPK pathway activation and accompanying ERK pathway inhibition after SA application was also tested.Results. We have found that saturated SA at apoptosis-inducing concentration (1 mM) activated the p38 MAPK signaling pathway MKK3/6→p38 MAPK→MAPKAPK-2 and inhibited the ERK signaling pathway c-Raf→MEK1/2→ERK1/2. The inhibition of p38 MAPK expression by siRNA silencing had no significant effect on cell viability or the level of phosphorylated ERK pathway members after SA administration. The inhibition of p38 MAPK activity by the specific inhibitor SB202190 resulted in noticeable activation of ERK pathway members after SA treatment but in no significant effect on cell viability. p38 MAPK overexpression by plasmid transfection produced no significant influence on cell viability or ERK pathway activation after SA exposure. The activation of p38 MAPK by the specific activator anisomycin led to apoptosis induction similar to application of SA (PARP cleavage and caspase-7, -8, and -9 activation) and in inhibition of ERK pathway members.Conclusions. We demonstrated that apoptosis-inducing concentrations of SA activate the p38 MAPK signaling pathway and that this activation could be involved in apoptosis induction by SA in the human pancreatic β-cells NES2Y. However, this involvement does not seem to play a key role. Crosstalk between p38 MAPK pathway activation and ERK pathway inhibition in NES2Y cells seems likely. Thus, the ERK pathway inhibition by p38 MAPK activation does not also seem to be essential for SA-induced apoptosis.

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Early growth response (EGR)-1 is required for timely cell-cycle entry and progression in hepatocytes after acute carbon tetrachloride exposure in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00544.2010 ◽

2011 ◽

Vol 300 (6) ◽

pp. G1124-G1131 ◽

Cited By ~ 23

Author(s):

Michele T. Pritchard ◽

Robert N. Malinak ◽

Laura E. Nagy

Keyword(s):

Phase Transition ◽

Cell Cycle ◽

Liver Injury ◽

Growth Response ◽

Early Growth ◽

S Phase ◽

Early Growth Response ◽

Cell Cycle Entry ◽

Tnf Α ◽

Toxic Liver Injury

Cell-cycle induction in hepatocytes protects from prolonged tissue damage after toxic liver injury. Early growth response ( Egr) -1−/− mice exhibit increased liver injury after carbon tetrachloride (CCl4) exposure and reduced TNF-α production. Because TNF-α is required for prompt cell-cycle induction after liver injury, here, we tested the hypothesis that Egr-1 is required for timely hepatocyte entry into the cell cycle after CCl4-induced liver injury. Acute liver injury was induced by a single injection of CCl4. Assays were employed to assess indices of the cell cycle in liver after CCl4 exposure. Bromodeoxyuridine incorporation peaked in wild-type mice at 48 h after CCl4 but was reduced by 80% in Egr-1−/− mice. Proliferating-cell nuclear-antigen immunohistochemistry revealed blocks in cell-cycle entry and progression to DNA synthesis in Egr-1-deficient mice 48 h after CCl4. Cyclin D, important for G0/G1 progression, was reduced at baseline and 36 h after CCl4. Cyclin E1, required for G1/S-phase transition, was reduced in Egr-1−/− mice 24 and 48 h after CCl4 exposure and was associated with reduced phosphorylation of the retinoblastoma protein. Proliferation in Egr-1−/− mice was delayed, rather than blocked, because indices of cell-cycle progression were restored 72 h after CCl4 exposure. We concluded that Egr-1 was required for prompt cell-cycle entry (G0- to G1-phase) and G1/S-phase transition after toxic liver injury. These data support the hypothesis that Egr-1 provides hepatoprotection in the CCl4-injured liver, attributable, in part, to timely cell-cycle induction and progression.

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The defense response of Caenorhabditis elegans to Cutibacterium acnes SK137 via the TIR-1-p38 MAPK signaling pathway

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbab218 ◽

2021 ◽

Author(s):

Ayano Tsuru ◽

Yumi Hamazaki ◽

Shuta Tomida ◽

Mohammad Shaokat Ali ◽

Eriko Kage-Nakadai

Keyword(s):

Caenorhabditis Elegans ◽

Signaling Pathway ◽

P38 Mapk ◽

Defense Response ◽

Mapk Pathway ◽

Defense Responses ◽

Mapk Signaling ◽

Dependent Manner ◽

Healthy Skin ◽

Cutibacterium Acnes

Abstract Cutibacterium acnes plays roles in both acne disease and healthy skin ecosystem. We observed that mutations in the tir-1/SARM1 and p38 MAPK cascade genes significantly shortened Caenorhabditis elegans lifespan upon Cutibacterium acnes SK137 infection. Antimicrobial molecules were induced by SK137 in a TIR-1-dependent manner. These results suggest that defense responses against SK137 involve the TIR-1-p38 MAPK pathway in Caenorhabditis elegans.

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p38 MAPK signaling pathway activation by phenyl benzoxime in SNU-306 cells causes induction of apoptosis

Microbial Pathogenesis ◽

10.1016/j.micpath.2018.10.021 ◽

2019 ◽

Vol 126 ◽

pp. 74-78 ◽

Cited By ~ 1

Author(s):

Wei Chen ◽

Yanni Tan ◽

Yu Zhang

Keyword(s):

Signaling Pathway ◽

P38 Mapk ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Pathway Activation ◽

Induction Of Apoptosis

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Phosphoinositide 3-Kinases p110α and p110β Regulate Cell Cycle Entry, Exhibiting Distinct Activation Kinetics in G1 Phase

Molecular and Cellular Biology ◽

10.1128/mcb.01786-07 ◽

2008 ◽

Vol 28 (8) ◽

pp. 2803-2814 ◽

Cited By ~ 34

Author(s):

Miriam Marqués ◽

Amit Kumar ◽

Isabel Cortés ◽

Ana Gonzalez-García ◽

Carmen Hernández ◽

...

Keyword(s):

Cell Cycle ◽

Tyrosine Kinases ◽

Control Cell ◽

Growth Factor Receptor ◽

Maximum Activity ◽

S Phase ◽

Selective Action ◽

Cell Cycle Entry ◽

Phosphoinositide 3 Kinase ◽

Phase Entry

ABSTRACT Phosphoinositide 3-kinase (PI3K) is an early signaling molecule that regulates cell growth and cell cycle entry. PI3K is activated immediately after growth factor receptor stimulation (at the G0/G1 transition) and again in late G1. The two ubiquitous PI3K isoforms (p110α and p110β) are essential during embryonic development and are thought to control cell division. Nonetheless, it is presently unknown at which point each is activated during the cell cycle and whether or not they both control S-phase entry. We found that p110α was activated first in G0/G1, followed by a minor p110β activity peak. In late G1, p110α activation preceded that of p110β, which showed the maximum activity at this time. p110β activation required Ras activity, whereas p110α was first activated by tyrosine kinases and then further induced by active Ras. Interference with p110α and -β activity diminished the activation of downstream effectors with different kinetics, with a selective action of p110α in blocking early G1 events. We show that inhibition of either p110α or p110β reduced cell cycle entry. These results reveal that PI3Kα and -β present distinct activation requirements and kinetics in G1 phase, with a selective action of PI3Kα at the G0/G1 phase transition. Nevertheless, PI3Kα and -β both regulate S-phase entry.

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