Activin Inhibits the Human Pit-1 Gene Promoter through the p38 Kinase Pathway in a Smad-Independent Manner

The pituitary transcription factor Pit-1 regulates hormonal production from the anterior pituitary gland. However, the mechanisms by which Pit-1 gene expression is regulated in humans are poorly understood. Activin, a member of the TGFβ superfamily, acts as a negative regulator of cell growth and prolactin gene expression in lactotrope cells. In this study, we show that activin negatively regulates the human Pit-1 gene promoter. We defined a 117-bp element within the Pit-1 promoter that is sufficient to relay these inhibitory effects. We further investigated the signaling pathways that mediate activin-induced inhibition of Pit-1 gene promoter in pituitary lactotrope cells. We found that the activin effects on Pit-1 gene regulation are Smad independent and require the p38 MAPK pathway. Specifically, blocking p38 kinase activity reverses activin-mediated inhibition of the Pit-1 gene promoter. Together, our results highlight the p38 MAPK pathway as a key regulator of activin function in pituitary lactotrope cells and further emphasizes the critical role played by activin in regulating hormonal production in the pituitary gland.

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Poly-L-Lactic Acid Increases Collagen Gene Expression and Synthesis in Cultured Dermal Fibroblast (Hs68) Through the p38 MAPK Pathway

Annals of Dermatology ◽

10.5021/ad.2019.31.1.97 ◽

2019 ◽

Vol 31 (1) ◽

pp. 97 ◽

Cited By ~ 2

Author(s):

Sung-Ae Kim ◽

Hyo-Seon Kim ◽

Jin-Woong Jung ◽

Sung-Il Suh ◽

Young-Wook Ryoo

Keyword(s):

Gene Expression ◽

Lactic Acid ◽

P38 Mapk ◽

Mapk Pathway ◽

Dermal Fibroblast ◽

Collagen Gene ◽

Collagen Gene Expression ◽

P38 Mapk Pathway

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Faculty Opinions recommendation of Microtubule depolymerization in Caenorhabditis elegans touch receptor neurons reduces gene expression through a p38 MAPK pathway.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.8934956.9491054 ◽

2011 ◽

Author(s):

Andrew Chisholm

Keyword(s):

Gene Expression ◽

Caenorhabditis Elegans ◽

P38 Mapk ◽

Mapk Pathway ◽

Microtubule Depolymerization ◽

P38 Mapk Pathway ◽

Touch Receptor Neurons ◽

Receptor Neurons

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Acquired resistance to zoledronic acid and the parallel acquisition of an aggressive phenotype are mediated by p38-MAP kinase activation in prostate cancer cells

Cell Death and Disease ◽

10.1038/cddis.2013.165 ◽

2013 ◽

Vol 4 (5) ◽

pp. e641-e641 ◽

Cited By ~ 43

Author(s):

M R Milone ◽

B Pucci ◽

F Bruzzese ◽

C Carbone ◽

G Piro ◽

...

Keyword(s):

Prostate Cancer ◽

Zoledronic Acid ◽

P38 Mapk ◽

Mapk Pathway ◽

Critical Role ◽

Resistance Index ◽

P38 Map Kinase ◽

Cross Resistance ◽

Mesenchymal Transition ◽

P38 Mapk Pathway

Abstract The nitrogen-containing bisphosphonates (N-BP) zoledronic acid (ZOL) inhibits osteoclast-mediated bone resorption, and it is used to prevent skeletal complications from bone metastases. ZOL has also demonstrated anticancer activities in preclinical models and, recently, in cancer patients, highlighting the interest in determining eventual mechanisms of resistance against this agent. In our study, we selected and characterised a resistant subline of prostate cancer (PCa) cells to better understand the mechanisms, by which tumour cells can escape the antitumour effect of ZOL. DU145R80-resistant cells were selected in about 5 months using stepwise increasing concentrations of ZOL from DU145 parental cells. DU145R80 cells showed a resistance index value of 5.5 and cross-resistance to another N-BP, pamidronate, but not to the non-nitrogen containing BP clodronate. Notably, compared with DU145 parental cells, DU145R80 developed resistance to apoptosis and anoikis, as well as overexpressed the anti-apoptotic protein Bcl-2 and oncoprotein c-Myc. Moreover, DU145R80 cells underwent epithelial to mesenchymal transition (EMT) and showed increased expression of the metalloproteases MMP-2/9, as well as increased invading capability. Interestingly, compared with DU145, DU145R80 cells also increased the gene expression and protein secretion of VEGF and the cytokines Eotaxin-1 and IL-12. At the molecular level, DU145R80 cells showed strong activation of the p38-MAPK-dependent survival pathway compared with parental sensitive cells. Moreover, using the p38-inhibitor SB203580, we completely reversed the resistance to ZOL, as well as EMT marker expression and invasion. Furthermore, SB203580 treatment reduced the expression of VEGF, Eotaxin-1, IL-12, MMP-9, Bcl-2 and c-Myc. Thus, for the first time, we demonstrate that the p38-MAPK pathway can be activated under continuous extensive exposure to ZOL in PCa cells and that the p38-MAPK pathway has a critical role in the induction of resistance, as well as in the acquisition of a more aggressive and invasive phenotype.

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Aquaporin-3 Attenuates Oxidative Stress-Induced Nucleus Pulposus Cell Apoptosis Through Regulating the P38 MAPK Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000494788 ◽

2018 ◽

Vol 50 (5) ◽

pp. 1687-1697 ◽

Cited By ~ 10

Author(s):

Yichun Xu ◽

Hui Yao ◽

Qiyou Wang ◽

Wenbin Xu ◽

Kaihua Liu ◽

...

Keyword(s):

Gene Expression ◽

Oxidative Damage ◽

P38 Mapk ◽

Cell Apoptosis ◽

Caspase 3 ◽

Mapk Pathway ◽

Aquaporin 3 ◽

P38 Mapk Pathway ◽

Intracellular Ros ◽

Cellular Apoptosis

Background/Aims: Previous studies have shown that oxidative damage is a main contributor to disc nucleus pulposus (NP) cell apoptosis. Aquaporin-3 (AQP-3) facilitates reactive oxygen species (ROS) scavenging and thus alleviates oxidative injury in other cells. This study aims to investigate the role and mechanism of AQP-3 in regulating NP cell apoptosis under oxidative damage. Methods: Rat NP cells were treated with H2O2 for 48 hours, while control NP cells were free of H2O2. Recombinant AQP-3 lentiviral vectors were used to investigate the effect of enhanced AQP-3 expression levels in NP cells. NP cell apoptosis was assessed by flow cytometry, caspase-3 activity, gene expression of apoptosis-related molecules (Bax, Bcl-2 and caspase-3), and protein expression of cellular apoptosis markers (cleaved PARP and cleaved caspase-3). Additionally, intracellular ROS content and activity of the p38 MAPK pathway were evaluated. Results: Compared with the control NP cells, oxidative damage in the treatment cells significantly increased cell apoptosis ratios and caspase-3 activity, upregulated gene expression of Bax and caspase-3, downregulated gene expression of Bcl-2, and increased protein expression of cleaved PARP and cleaved caspase-3, as well as increased intracellular ROS content and activity of the p38 MAPK pathway. However, AQP-3 overexpression partly alleviated cell apoptosis, decreased intracellular ROS content, and inhibited the p38 MAPK pathway in NP cells under oxidative damage. Conclusion: Oxidative damage can significantly downregulate AQP-3 expression. Enhancing AQP-3 expression in NP cells partly attenuates cellular apoptosis through regulating the p38 MAPK pathway under oxidative damage.

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Microtubule depolymerization in Caenorhabditis elegans touch receptor neurons reduces gene expression through a p38 MAPK pathway

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1101360108 ◽

2011 ◽

Vol 108 (10) ◽

pp. 3982-3987 ◽

Cited By ~ 63

Author(s):

A. Bounoutas ◽

J. Kratz ◽

L. Emtage ◽

C. Ma ◽

K. C. Nguyen ◽

...

Keyword(s):

Gene Expression ◽

Caenorhabditis Elegans ◽

P38 Mapk ◽

Mapk Pathway ◽

Microtubule Depolymerization ◽

P38 Mapk Pathway ◽

Touch Receptor Neurons ◽

Receptor Neurons

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Mechanism of AP-1-mediated gene expression by select organochlorines through the p38 MAPK pathway

Carcinogenesis ◽

10.1093/carcin/bgh009 ◽

2003 ◽

Vol 25 (2) ◽

pp. 249-261 ◽

Cited By ~ 62

Author(s):

D. E. Frigo

Keyword(s):

Gene Expression ◽

P38 Mapk ◽

Mapk Pathway ◽

P38 Mapk Pathway

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Polyunsaturated fatty acids and p38-MAPK link metabolic reprogramming to cytoprotective gene expression during dietary restriction

Nature Communications ◽

10.1038/s41467-020-18690-4 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Manish Chamoli ◽

Anita Goyala ◽

Syed Shamsh Tabrez ◽

Atif Ahmed Siddiqui ◽

Anupama Singh ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acids ◽

Polyunsaturated Fatty Acids ◽

Life Span ◽

P38 Mapk ◽

Dietary Restriction ◽

Mapk Pathway ◽

Metabolic Reprogramming ◽

Metabolic State ◽

P38 Mapk Pathway

Abstract The metabolic state of an organism instructs gene expression modalities, leading to changes in complex life history traits, such as longevity. Dietary restriction (DR), which positively affects health and life span across species, leads to metabolic reprogramming that enhances utilisation of fatty acids for energy generation. One direct consequence of this metabolic shift is the upregulation of cytoprotective (CyTP) genes categorized in the Gene Ontology (GO) term of “Xenobiotic Detoxification Program” (XDP). How an organism senses metabolic changes during nutritional stress to alter gene expression programs is less known. Here, using a genetic model of DR, we show that the levels of polyunsaturated fatty acids (PUFAs), especially linoleic acid (LA) and eicosapentaenoic acid (EPA), are increased following DR and these PUFAs are able to activate the CyTP genes. This activation of CyTP genes is mediated by the conserved p38 mitogen-activated protein kinase (p38-MAPK) pathway. Consequently, genes of the PUFA biosynthesis and p38-MAPK pathway are required for multiple paradigms of DR-mediated longevity, suggesting conservation of mechanism. Thus, our study shows that PUFAs and p38-MAPK pathway function downstream of DR to help communicate the metabolic state of an organism to regulate expression of CyTP genes, ensuring extended life span.

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Research on Roles of Mongolian Medical Warm Acupuncture in Inhibiting p38 MAPK Activation and Apoptosis of Nucleus Pulposus Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/6571320 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8

Author(s):

Sha Li ◽

Lidao Bao ◽

Lengge Si ◽

Xiaohui Wang ◽

Agula Bo

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Extracellular Matrix ◽

Matrix Metalloproteinase ◽

Nucleus Pulposus ◽

P38 Mapk ◽

Mapk Pathway ◽

Active Oxygen ◽

Nucleus Pulposus Cells ◽

P38 Mapk Pathway

Background. Mongolian medical warm acupuncture has a desirable therapeutic effect on sciatica. Apoptosis of the nucleus pulposus cells is considered to play an important role in sciatica. Evidence has demonstrated that oxidative stress and its induced activation of the signaling pathways play important roles in sciatica. However, further research is expected to reveal whether Mongolian medical warm acupuncture can inhibit the apoptosis of nucleus pulposus cells and oxidative stress. Objective. To study the effect of the p38 MAPK pathway activated by the generated ROS on apoptosis and the expression of the genes related to the balance of the extracellular matrix metabolism during treatment of sciatica with Mongolian medical warm acupuncture. Method. The volume of the active oxygen generated in the nucleus pulposus cells was detected following intervention of Mongolian medical warm acupuncture. The p38 MAPK phosphorylation level was detected with Western blot. The genes are related to the metabolism of the nucleus pulposus extracellular matrix. Result. Mongolian medical warm acupuncture reduced the active oxygen within the nucleus pulposus cells and inhibited the activation of the p38 MAPK pathway (P=0.013). Meanwhile, it upregulated the gene expression of Type II collagen, aggrecan, Sox-9, and tissue matrix metalloproteinase reagent 1 (P-0.015; P=0.025; P=0.031; P=0.045) and downregulated the gene expression of matrix metalloproteinase 3 (P=0.015). Conclusion. Mongolian medical warm acupuncture may inhibit apoptosis of nucleus pulposus cells and activation of the extracellular matrix decomposition metabolism pathway and promote its anabolism. This process may rely on the oxidative stress matrix of the p38 MAPK pathway.

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