Activation of p38 MAPK induces cell cycle arrest via inhibition of Raf/ERK pathway during muscle differentiation

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) Vpr protein has important functions in advancing HIV pathogenesis via several effects on the host cell. Vpr mediates nuclear import of the preintegration complex, induces host cell apoptosis, and inhibits cell cycle progression at G2, which increases HIV gene expression. Some of Vpr's activities have been well described, but some functions, such as cell cycle arrest, are not yet completely characterized, although components of the ATR DNA damage repair pathway and the Cdc25C and Cdc2 cell cycle control mechanisms clearly play important roles. We investigated the mechanisms underlying Vpr-mediated cell cycle arrest by examining global cellular gene expression profiles in cell lines that inducibly express wild-type and mutant Vpr proteins. We found that Vpr expression is associated with the down-regulation of genes in the MEK2-ERK pathway and with decreased phosphorylation of the MEK2 effector protein ERK. Exogenous provision of excess MEK2 reverses the cell cycle arrest associated with Vpr, confirming the involvement of the MEK2-ERK pathway in Vpr-mediated cell cycle arrest. Vpr therefore appears to arrest the cell cycle at G2/M through two different mechanisms, the ATR mechanism and a newly described MEK2 mechanism. This redundancy suggests that Vpr-mediated cell cycle arrest is important for HIV replication and pathogenesis. Our findings additionally reinforce the idea that HIV can optimize the host cell environment for viral replication.

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The Chalcone Flavokawain B Induces G2/M Cell-Cycle Arrest and Apoptosis in Human Oral Carcinoma HSC-3 Cells through the Intracellular ROS Generation and Downregulation of the Akt/p38 MAPK Signaling Pathway

Journal of Agricultural and Food Chemistry ◽

10.1021/jf205053r ◽

2012 ◽

Vol 60 (9) ◽

pp. 2385-2397 ◽

Cited By ~ 70

Author(s):

You-Cheng Hseu ◽

Meng-Shiou Lee ◽

Chi-Rei Wu ◽

Hsin-Ju Cho ◽

Kai-Yuan Lin ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Signaling Pathway ◽

P38 Mapk ◽

Mapk Signaling ◽

Oral Carcinoma ◽

Ros Generation ◽

M Cell ◽

Cycle Arrest ◽

Intracellular Ros

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Podophyllotoxin Induces ROS-Mediated Apoptosis and Cell Cycle Arrest in Human Colorectal Cancer Cells via p38 MAPK Signaling

Biomolecules & Therapeutics ◽

10.4062/biomolther.2021.143 ◽

2021 ◽

Author(s):

Seung-On Lee ◽

Sang Hoon Joo ◽

Ah-Won Kwak ◽

Mee-Hyun Lee ◽

Ji-Hye Seo ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

P38 Mapk ◽

Mapk Signaling ◽

Human Colorectal Cancer ◽

Cycle Arrest ◽

Colorectal Cancer Cells ◽

Human Colorectal Cancer Cells

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Berberine and Evodiamine Synergically Exert Anti-colorectal Cancer Effeccts via P38/MAPK/MAPKAPK2/HSP27 Signaling Pathway

10.21203/rs.3.rs-1166461/v1 ◽

2022 ◽

Author(s):

Ningning Chen ◽

Yifang Jiang ◽

Yi Yang ◽

Ziyi Zhao ◽

Chong Xiao ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Cycle ◽

Colon Cancer ◽

Natural Products ◽

Cell Cycle Arrest ◽

P38 Mapk ◽

Synergistic Effects ◽

Migration And Invasion ◽

Antitumor Effects ◽

Cycle Arrest

Abstract Objective: Combinatorial natural products have high application potential for treatment of complex diseases owing to their synergistic effects and multi-targeting effect. However, studies have not explored the therapeutic effect and the synergetic mechanisms of action combinations of natural products. The present study aimed sought to evaluate the synergistic antitumor effects of a combination of Berberine and Evodiamine, and explore the drug effect on proliferation, migration, invasion of HCT116 and RKO human colorectal cancer cells. Results: The effect of berberine and evodiamine at a specific paired dose (BER30μM, EVO 0.8μM) was explored. A combination of berberine and evodiamine had no effect on activity and proliferation of HCT116 and RKO cells. The combination regulates the cell cycle of HCT116 and RKO cells at different cell phases. Berberine mainly blocked the cell cycle at G0/G1 phase, whereas evodiamine induced cell cycle arrest at G2/M phase. The results showed that the combined effect of berberine and evodiamine does not offset each other, but plays a synergistic role in regulation of colon cancer cell cycle. Western blot analysis showed that the combination of berberine and evodiamine regulated cell cycle by downregulating expression of cdc25c and upregulating expression of p21. The combination significantly inhibited cell migration and invasion by regulating EMT related proteins, upregulating expression of E-cadherin and downregulating expression of N-cadherin. The combination of berberine and evodiamine significantly inhibited phosphorylation of P38 MAPK in HCT116 and RKO cells, and further inhibited phosphorylation of the downstream MAPKAPK2 and HSP27, thus playing a synergistic anti-colon cancer role.Conclusion: Berberine and Evodiamine exhibit synergistic antitumor effects by suppressing cell proliferation, inducing cell cycle arrest and inhibiting EMT by modulating P38MAPK /MAPKAPK2/HSP27 pathway.Significance of the study: To illustrate the potential mechanism of formula-based combination of natural products, and explore the potential applications of the combination and possible antitumor therapeutic targets.

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p38 Mitogen-Activated Protein Kinase- and HuR-Dependent Stabilization of p21Cip1 mRNA Mediates the G1/S Checkpoint

Molecular and Cellular Biology ◽

10.1128/mcb.00210-09 ◽

2009 ◽

Vol 29 (16) ◽

pp. 4341-4351 ◽

Cited By ~ 150

Author(s):

Vanesa Lafarga ◽

Ana Cuadrado ◽

Isabel Lopez de Silanes ◽

Rocio Bengoechea ◽

Oscar Fernandez-Capetillo ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Protein Kinase ◽

Cell Cycle Arrest ◽

P38 Mapk ◽

Mitogen Activated Protein Kinase ◽

Γ Radiation ◽

Cycle Arrest ◽

Mitogen Activated Protein

ABSTRACT Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the G2/M cell cycle arrest induced by DNA damage, but little is known about the role of this signaling pathway in the G1/S transition. Upregulation of the cyclin-dependent kinase inhibitor p21Cip1 is thought to make a major contribution to the G1/S cell cycle arrest induced by γ radiation. We show here that inhibition of p38 MAPK impairs p21Cip1 accumulation and, as a result, the ability of cells to arrest in G1 in response to γ radiation. We found that p38 MAPK induces p21Cip1 mRNA stabilization, without affecting its transcription or the stability of the protein. In particular, p38 MAPK phosphorylates the mRNA binding protein HuR on Thr118, which results in cytoplasmic accumulation of HuR and its enhanced binding to the p21Cip1 mRNA. Our findings help to understand the emerging role of p38 MAPK in the cellular responses to DNA damage and reveal the existence of p53-independent networks that cooperate in modulating p21Cip1 levels at the G1/S checkpoint.

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