p38 MAPK α and β isoforms differentially regulate plasma membrane localization of MRP2

In hepatocytes, cAMP both activates p38 mitogen-activated protein kinase (MAPK) and increases the amount of multidrug resistance-associated protein-2 (MRP2) in the plasma membrane (PM-MRP2). Paradoxically, taurolithocholate (TLC) activates p38 MAPK but decreases PM-MRP2 in hepatocytes. These opposing effects of cAMP and TLC could be mediated via different p38 MAPK isoforms (α and β) that are activated differentially by upstream kinases (MKK3, MKK4, and MKK6). Thus we tested the hypothesis that p38α MAPK and p38β MAPK mediate increases and decreases in PM-MRP2 by cAMP and TLC, respectively. Studies were conducted in hepatocytes isolated from C57BL/6 wild-type (WT) and MKK3-knockout (MKK3−/−) mice and in a hepatoma cell line (HuH7) that overexpresses sodium-taurocholate cotransporting polypeptide (NTCP) (HuH-NTCP). Cyclic AMP activated MKK3, p38 MAPK, and p38α MAPK and increased PM-MRP2 in WT hepatocytes, but failed to activate p38α MAPK or increase PM-MRP2 in MKK3−/− hepatocytes. In contrast to cAMP, TLC activated total p38 MAPK but decreased PM-MRP2, and did not activate MKK3 or p38α MAPK in WT hepatocytes. In MKK3−/− hepatocytes, TLC still decreased PM-MRP2 and activated p38 MAPK, indicating that these effects are not MKK3-dependent. Additionally, TLC activated MKK6 in MKK3−/− hepatocytes, and small interfering RNA knockdown of p38β MAPK abrogated TLC-mediated decreases in PM-MRP2 in HuH-NTCP cells. Taken together, these results suggest that p38α MAPK facilitates plasma membrane insertion of MRP2 by cAMP, whereas p38β MAPK mediates retrieval of PM-MRP2 by TLC.

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Adaphostin promotes caffeine-evoked autocrine Fas-mediated death pathway activation in Bcr/Abl-positive leukaemia cells

Biochemical Journal ◽

10.1042/bj20110725 ◽

2011 ◽

Vol 439 (3) ◽

pp. 453-470 ◽

Cited By ~ 2

Author(s):

Wen-Hsin Liu ◽

Long-Sen Chang

Keyword(s):

P38 Mapk ◽

K562 Cells ◽

Mitogen Activated Protein Kinase ◽

Pathway Activation ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

P38α Mapk ◽

Activating Transcription Factor ◽

Leukaemia Therapy ◽

Jnk Activation

The present study was conducted to verify whether caffeine is beneficial for improving leukaemia therapy. Co-treatment with adaphostin (a Bcr/Abl inhibitor) was found to potentiate caffeine-induced Fas/FasL up-regulation. Although adaphostin did not elicit ASK1 (apoptosis signal-regulating kinase 1)-mediated phosphorylation of p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase), co-treatment with adaphostin notably increased p38 MAPK/JNK activation in caffeine-treated cells. Suppression of p38 MAPK and JNK abrogated Fas/FasL up-regulation in caffeine- and caffeine/adaphostin-treated cells. Compared with caffeine, adaphostin markedly suppressed Akt/ERK (extracellular-signal-regulated kinase)-mediated MKP-1 (MAPK phosphatase 1) protein expression in K562 cells. MKP-1 down-regulation eventually elucidated the enhanced effect of adaphostin on p38 MAPK/JNK activation and subsequent Fas/FasL up-regulation in caffeine-treated cells. Knockdown of p38α MAPK and JNK1, ATF-2 (activating transcription factor 2) and c-Jun by siRNA (small interfering RNA) proved that p38α MAPK/ATF-2 and JNK1/c-Jun pathways were responsible for caffeine-evoked Fas/FasL up-regulation. Moreover, Ca2+ and ROS (reactive oxygen species) were demonstrated to be responsible for ASK1 activation and Akt/ERK inactivation respectively in caffeine- and caffeine/adaphostin-treated cells. Likewise, adaphostin functionally enhanced caffeine-induced Fas/FasL up-regulation in leukaemia cells that expressed Bcr/Abl. Taken together, the results of the present study suggest a therapeutic strategy in improving the efficacy of adaphostin via Fas-mediated death pathway activation in Bcr/Abl-positive leukaemia.

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An Effective Antiviral Approach Targeting Hepatitis B Virus with NJK14047, a Novel and Selective Biphenyl Amide p38 Mitogen-Activated Protein Kinase Inhibitor

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00214-17 ◽

2017 ◽

Vol 61 (8) ◽

Cited By ~ 3

Author(s):

So-Young Kim ◽

Hong Kim ◽

Sang-Won Kim ◽

Na-Rae Lee ◽

Chae-Min Yi ◽

...

Keyword(s):

Hepatitis B Virus ◽

Protein Kinase ◽

Hepatitis B ◽

P38 Mapk ◽

Sodium Taurocholate ◽

Therapeutic Strategies ◽

Host Factors ◽

Mitogen Activated Protein Kinase ◽

B Virus ◽

Mitogen Activated Protein

ABSTRACT Despite recent advances in therapeutic strategies against hepatitis B virus (HBV) infection, chronic hepatitis B remains a major global health burden. Recent studies have shown that targeting host factors instead of viral factors can be an effective antiviral strategy with low risk of the development of resistance. Efforts to identify host factors affecting viral replication have identified p38 mitogen-activated protein kinase (MAPK) as a possible target for antiviral strategies against various viruses, including HBV. Here, a series of biphenyl amides were synthesized as novel p38 MAPK selective inhibitors and assessed for their anti-HBV activities. The suppression of HBV surface antigen (HBsAg) production by these compounds was positively correlated with p38 MAPK-inhibitory activity. The selected compound NJK14047 displayed significant anti-HBV activity, as determined by HBsAg production, HBeAg secretion, and HBV production. NJK14047 efficiently suppressed the secretion of HBV antigens and HBV particles from HBV genome-transfected cells and HBV-infected sodium taurocholate cotransporting polypeptide-expressing human hepatoma cells. Furthermore, NJK14047 treatment resulted in a significant decrease of pregenomic RNA and covalently closed circular DNA (cccDNA) of HBV in HBV-harboring cells, indicating its ability to inhibit HBV replication. Considering that suppression of HBsAg secretion and elimination of cccDNA of HBV are the major aims of anti-HBV therapeutic strategies, the results suggested the potential use of these compounds as a novel class of anti-HBV agents targeting host factors critical for viral infection.

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The p38 Mitogen-Activated Protein Kinase Regulates 11β-Hydroxysteroid Dehydrogenase Type 2 (11β-HSD2) Expression in Human Trophoblast Cells through Modulation of 11β-HSD2 Messenger Ribonucleic Acid Stability

Endocrinology ◽

10.1210/en.2009-0479 ◽

2009 ◽

Vol 150 (9) ◽

pp. 4278-4286 ◽

Cited By ~ 29

Author(s):

Anju Sharma ◽

Haiyan Guan ◽

Kaiping Yang

Keyword(s):

P38 Mapk ◽

Hydroxysteroid Dehydrogenase ◽

Mitogen Activated Protein Kinase ◽

Trophoblast Cells ◽

Human Trophoblast ◽

Messenger Ribonucleic Acid ◽

Mitogen Activated Protein ◽

Important Regulator ◽

Interfering Rna

Abstract The placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2; encoded by the HSD11B2 gene) has emerged as a key player in controlling fetal development, but its regulation is incompletely understood. Here we identified p38 MAPK as an important regulator of placental 11β-HSD2. We showed that inhibition of p38 MAPK with the pharmacological inhibitor SB202190 led to an approximately 50% reduction in 11β-HSD2 activity, protein, and mRNA in primary human placental trophoblast cells. Furthermore, the effect of SB202190 was confirmed by the use of two additional p38 inhibitors, SB203580 and SB220025. In addition, SB202190 decreased the half-life of 11β-HSD2 mRNA without altering the HSD11B2 promoter activity, indicating that p38 MAPK regulates placental 11β-HSD2 expression through modulation of 11β-HSD2 mRNA stability. Importantly, small interfering RNA-mediated knockdown of p38α caused a 50% reduction in 11β-HSD2 activity, suggesting that p38α is the primary p38 isoform involved. Taken together, these findings suggest a novel pathway controlling placental 11β-HSD2 expression resulting from the activation of p38 MAPK. Given that p38α is abundantly expressed in the human placenta in which its function is largely unknown, our present study also reveals 11β-HSD2 as an important target through which p38α may regulate human placental function and consequently fetal growth and development.

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Inhibiting MAPK14 showed anti-prolactinoma effect

10.21203/rs.3.rs-22129/v3 ◽

2020 ◽

Author(s):

Qiaoyan Ding ◽

Yu Zhang ◽

Li Ma ◽

Yong-gang Chen ◽

Jin-hu Wu ◽

...

Keyword(s):

Pituitary Gland ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Gh3 Cells ◽

Immunofluorescence Analysis ◽

Mitogen Activated Protein ◽

P38α Mapk ◽

Interfering Rna

Abstract Background The specific underlying pathogenesis of prolactinoma has not been clarified yet, to the best of our knowledge. p38 mitogen-activated protein kinase (MAPK) signaling including p38α MAPK (MAPK14), p38β (MAPK11), p38γ (MAPK12) and p38δ (MAPK13) is associated with the development and progression of several types of cancer.Methods Immunofluorescence analysis was performed on the prolactin (PRL) and MAPK14 expressions of pituitary gland in C57BL/6 mice and human prolactinoma specimen. In the present study, the role of MAPK14 in prolactinoma was determined using estradiol-induced mice and dopamine D2 receptor knockout (DRD2-/-) mice models in C57BL/6 wild-type (WT), MAPK14-/- and DRD2-/-MAPK14+/- mice. GH3 cells were transfected with different sets of MAPK14 small interfering RNA, which to study MAPK14 and PRL expression in GH3 cells.Results Immunofluorescence analysis showed that PRL and MAPK14 expression were colocalized and increased in the pituitary gland of mice and human prolactinoma specimen compared with the control specimen. It was shown that PRL and MAPK14 expression was colocalized and increased significantly in the pituitary gland of estradiol-injected prolactinoma mice compared with the control mice. Knockout of MAPK14 significantly inhibited tumor overgrowth, and PRL expression was decreased in estradiol-induced mice. Furthermore, MAPK14 knockout of DRD2-/-MAPK14+/- mice significantly reduced the overgrowth of pituitary gland and PRL production and secretion compared with DRD2-/- mice. MAPK14 knockout using siRNA inhibited PRL production in GH3 cells.Conclusion These results suggest that MAPK14 serves a promoting role in the formation of prolactinoma, and highlights the potential of MAPK14 as a potential therapeutic target in the treatment of prolactinoma.

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Abstract 1172: Neointima Formation is Dependent on p38α Mitogen-Activated Protein Kinase

Circulation ◽

10.1161/circ.116.suppl_16.ii_237 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Brandon M Proctor ◽

Anthony J Muslin

Keyword(s):

P38 Mapk ◽

Carotid Arteries ◽

Thymidine Incorporation ◽

Fold Increase ◽

Arterial Injury ◽

Mitogen Activated Protein Kinase ◽

Neointima Formation ◽

Mapk Activity ◽

Mitogen Activated Protein ◽

P38α Mapk

Neointima formation frequently occurs after arterial injury and is responsible for substantial human morbidity. We previously demonstrated that the intracellular linker protein Grb2 is required for neointima formation, and that Grb2 regulates p38α mitogen-activated protein kinase (MAPK) activation in vascular smooth muscle cells (SMCs). In this work, the role of p38α MAPK in neointima formation was examined. In vitro experiments showed that pharmacological inhibition of p38 MAPK activity in cultured SMCs blocked platelet-derived growth factor (PDGF)-stimulated DNA replication and cell proliferation. Specifically, in control SMCs, overnight stimulation with PDGF induced an 11.8-fold increase in thymidine incorporation and a 1.9 fold increase in cell number. However, inhibition of p38 MAPK activity reduced PDGF-induced thymidine incorporation to 2.8-fold (P = 0.0006) and completely blocked PDGF-stimulated cell proliferation (P = 0.0001). Also, p38 MAPK activity was required for PDGF-induced inactivation of the retinoblastoma tumor suppressor protein, Rb, and induction of mini-chromosome maintenance protein-6 (MCM6), a fundamental regulator of DNA replication. Next, compound transgenic mice were generated with doxycycline (Dox)-inducible, SMC-specific expression of a dominant-negative form of p38α MAPK (SMC-DN-p38α ). Dox induced robust expression of DN-p38α mRNA and protein in the aorta and carotid arteries of compound transgenic mice, and inactivation of native, arterial p38 MAPK. SMC-DN-p38α and single transgenic, control mice were subjected to carotid injury by use of an epoxy resin-beaded probe. After 21 days, control mice developed robust neointima formation that frequently resulted in an occlusive lesion with a mean neointima/media ratio of 2.62 (N = 8). In contrast, SMC-DN-p38α mice were resistant to the development of neointima. Specifically, neointima/media ratio was reduced to 0.63 for SMC-DN-p38α mice (N = 12; P = 0.045). In addition, compared to control mice, injured carotid arteries of SMC-DN-p38α mice showed defective p38 MAPK activation in SMCs of the tunica media. Our results demonstrate that vascular SMC p38α MAPK is required for neointima formation after arterial injury.

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Inhibiting MAPK14 showed anti-prolactinoma effect

10.21203/rs.3.rs-22129/v2 ◽

2020 ◽

Author(s):

Qiaoyan Ding ◽

Yu Zhang ◽

Li Ma ◽

Yong-gang Chen ◽

Jin-hu Wu ◽

...

Keyword(s):

Pituitary Gland ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Gh3 Cells ◽

Immunofluorescence Analysis ◽

Mitogen Activated Protein ◽

P38α Mapk ◽

Interfering Rna

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Phosphorylation of Fibroblast Growth Factor (FGF) Receptor 1 at Ser777 by p38 Mitogen-Activated Protein Kinase Regulates Translocation of Exogenous FGF1 to the Cytosol and Nucleus

Molecular and Cellular Biology ◽

10.1128/mcb.02117-07 ◽

2008 ◽

Vol 28 (12) ◽

pp. 4129-4141 ◽

Cited By ~ 37

Author(s):

Vigdis Sørensen ◽

Yan Zhen ◽

Malgorzata Zakrzewska ◽

Ellen Margrethe Haugsten ◽

Sébastien Wälchli ◽

...

Keyword(s):

Growth Factor ◽

Protein Kinase ◽

Fibroblast Growth Factor ◽

P38 Mapk ◽

Activity Level ◽

Mitogen Activated Protein Kinase ◽

Target Cells ◽

Fibroblast Growth ◽

Mitogen Activated Protein ◽

P38α Mapk

ABSTRACT Exogenous fibroblast growth factor 1 (FGF1) signals through activation of transmembrane FGF receptors (FGFRs) but may also regulate cellular processes after translocation to the cytosol and nucleus of target cells. Translocation of FGF1 occurs across the limiting membrane of intracellular vesicles and is a regulated process that depends on the C-terminal tail of the FGFR. Here, we report that translocation of FGF1 requires activity of the α isoform of p38 mitogen-activated protein kinase (MAPK). FGF1 translocation was inhibited after chemical inhibition of p38 MAPK or after small interfering RNA knockdown of p38α. Translocation was increased after stimulation of p38 MAPK with anisomycin, mannitol, or H2O2. The activity level of p38 MAPK was not found to affect endocytosis or intracellular sorting of FGF1/FGFR1. Instead, we found that p38 MAPK regulates FGF1 translocation by phosphorylation of FGFR1 at Ser777. The FGFR1 mutation S777A abolished FGF1 translocation, while phospho-mimetic mutations of Ser777 to Asp or Glu allowed translocation to take place and bypassed the requirement for active p38 MAPK. Ser777 in FGFR1 was directly phosphorylated by p38α in a cell-free system. These data demonstrate a crucial role for p38α MAPK in the regulated translocation of exogenous FGF1 into the cytosol/nucleus, and they reveal a specific role for p38α MAPK-mediated serine phosphorylation of FGFR1.

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Cyclic AMP stimulates Mrp2 translocation by activating p38α MAPK in hepatic cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00506.2009 ◽

2010 ◽

Vol 298 (5) ◽

pp. G667-G674 ◽

Cited By ~ 12

Author(s):

Christopher M. Schonhoff ◽

Cynthia R. L. Webster ◽

M. Sawkat Anwer

Keyword(s):

Cyclic Amp ◽

P38 Mapk ◽

Hepatoma Cell ◽

Specific Inhibitor ◽

Rat Hepatocytes ◽

Dominant Negative ◽

Hepatoma Cell Line ◽

Mapk Activity ◽

Hepatic Cells ◽

P38α Mapk

Cyclic AMP (cAMP) induces translocation of multidrug resistant protein 2 (Mrp2) to the canalicular membrane and activates p38 MAPK in rat hepatocytes. In this study, we tested the hypothesis that cAMP-induced Mrp2 translocation may be mediated via p38 MAPK. Studies were conducted in rat hepatocytes and in a human hepatoma cell line, HuH-7. In rat hepatocytes, cAMP increased Mrp2 translocation and p38 MAPK activity. These effects of cAMP were inhibited by SB203580, an inhibitor of p38 MAPK. Wortmannin, a specific inhibitor of phosphoinositide-3-kinase (PI3K), did not inhibit cAMP induced activation of p38 MAPK, indicating PI3K-independent activation of p38 MAPK by cAMP. To further define the role of p38 MAPK, molecular approaches were used to up- or downregulate p38 MAPK activity in HuH-7 cells using constitutively active (CA) and dominant-negative (DN) MAPK kinase 3 and 6 (MKK3/6). MKK3/6 are upstream kinases responsible for the activation of p38 MAPK. Cells transfected with CAMKK6 showed increased p38 MAPK activity and MRP2 translocation compared with empty vector. cAMP-induced activation of p38 MAPK was inhibited in cells transfected with DNMKK3/6 and DNMKK3, but not with DNMKK6. DNMKK3/6 and DNMKK3 also inhibited cAMP-induced MRP2 translocation. cAMP selectively activated p38α MAPK in HuH-7 cells. Knockdown of p38α MAPK by short heterodimer RNA resulted in decreased level of p38 MAPK and failure of cAMP to stimulate MRP2 translocation. Taken together, these results suggest that cAMP-induced MRP2 translocation in hepatic cells is mediated via PI3K-independent and MKK3-mediated activation of p38α MAPK.

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