scholarly journals Combined De-Repression of Chemoresistance Associated Mitogen-Activated Protein Kinase 14 and Activating Transcription Factor 2 by Loss of microRNA-622 in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1183
Author(s):  
Valerie Fritz ◽  
Lara Malek ◽  
Anne Gaza ◽  
Laura Wormser ◽  
Majken Appel ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcription Factor ◽  
Protein Kinase ◽  
Target Genes ◽  
Resistant Cell ◽  
Mitogen Activated Protein Kinase ◽  
Erk Activation ◽  
Mitogen Activated Protein ◽  
Collateral Pathway ◽  
Activating Transcription Factor

Chemoresistance is a major hallmark driving the progression and poor prognosis of hepatocellular carcinoma (HCC). Limited chemoresponse of HCC was demonstrated to be mediated by mitogen-activated protein kinase 14 (MAPK14) and activating transcription factor 2 (ATF2). Recently, we have demonstrated loss of control of RAS-RAF-ERK-signaling as a consequence of miR-622 downregulation in HCC. However, the majority of target genes of this potent tumorsuppressive microRNA had remained elusive. The MAPK14-ATF2-axis represents a collateral pathway ensuring persisting ERK-activation in the presence of sorafenib-mediated RAF-inhibition. In contrast to the function of the MAPK14-ATF2-axis, both the expression and regulation of MAPK14 and ATF2 in human HCC remained to be clarified. We found combined overexpression of MAPK14 and ATF2 in human HCC cells, tissues and in sorafenib resistant cell lines. High expression of MAPK14 and ATF2 was associated with reduced overall survival in HCC patients. Deciphering the molecular mechanism promoting combined upregulation of MAPK14 and ATF2 in HCC, we revealed that miR-622 directly targets both genes, resulting in combined de-repression of the MAPK14-ATF2-axis. Together, miR-622 represents a superior regulator of both RAS-RAF-ERK as well as MAPK14-ATF2-signaling pathways in liver cancer.

scholarly journals Helicobacter pylori VacA Enhances Prostaglandin E2 Production through Induction of Cyclooxygenase 2 Expression via a p38 Mitogen-Activated Protein Kinase/Activating Transcription Factor 2 Cascade in AZ-521 Cells

2007 ◽  
Vol 75 (9) ◽  
pp. 4472-4481 ◽  
Author(s):  
Junzo Hisatsune ◽  
Eiki Yamasaki ◽  
Masaaki Nakayama ◽  
Daisuke Shirasaka ◽  
Hisao Kurazono ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Transcription Factor ◽  
Protein Kinase ◽  
P38 Mapk ◽  
Cyclooxygenase 2 ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Mitogen Activated Protein ◽  
Cox 2 ◽  
Activating Transcription Factor

ABSTRACT Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase 2 (COX-2) mRNA in a time- and dose-dependent manner. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erk1/2 cascade, partially suppressed the increase. Consistent with involvement of p38 MAPK, VacA-induced accumulation of COX-2 mRNA was reduced in AZ-521 cells overexpressing a dominant-negative p38 MAPK (DN-p38). Phosphatidylinositol-specific phospholipase C, which inhibits VacA-induced p38 MAPK activation, blocked VacA-induced COX-2 expression. In parallel with COX-2 expression, VacA increased prostaglandin E2 (PGE2) production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE2 production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription of a COX-2 promoter reporter gene and activated a COX-2 promoter containing mutated NF-κB or NF-interleukin-6 sites but not a mutated cis-acting replication element (CRE) site, suggesting direct involvement of the activating transcription factor 2 (ATF-2)/CREB-binding region in VacA-induced COX-2 promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-small interfering RNA duplexes resulted in suppression of COX-2 expression. Thus, VacA enhances PGE2 production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK/ATF-2 cascade, leading to activation of the CRE site in the COX-2 promoter.

scholarly journals Requirement of the p38 mitogen-activated protein kinase signalling pathway for the induction of the 78 kDa glucose-regulated protein/immunoglobulin heavy-chain binding protein by azetidine stress: activating transcription factor 6 as a target for stress-induced phosphorylation

2002 ◽  
Vol 366 (3) ◽  
pp. 787-795 ◽  
Author(s):  
Shengzhan LUO ◽  
Amy S. LEE
Keyword(s):  
Signal Transduction ◽  
Transcription Factor ◽  
Protein Kinase ◽  
Er Stress ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Grp78 Promoter ◽  
Activating Transcription Factor ◽  
Glucose Regulated Protein

Malfolded protein formation and perturbance of calcium homoeostasis results in the induction of the endoplasmic reticulum (ER) chaperone protein, namely the 78kDa glucose-regulated protein (GRP78)/immunoglobulin heavy-chain binding protein. Various ER stress inducers can activate grp78, but signal transduction mechanisms are not well understood. We report in the present study that the induction of endogenous grp78 mRNA by the amino acid analogue azetidine (AzC) requires the integrity of a signal transduction pathway mediated by p38 mitogen-activated protein kinase (p38 MAPK). In contrast, induction of grp78 by thapsigargin that depletes the ER calcium storage can occur even when the p38 MAPK pathway is blocked. Treatment of cells with AzC results in the sustained activation of p38 MAPK. We identified an ER transmembrane activating transcription factor 6 (ATF6) as a target of p38 MAPK phosphorylation in AzC-treated cells. ATF6 undergoes proteolytic cleavage on AzC treatment, releasing a nuclear form that is an activator of the grp78 promoter. We show here that constitutively active mitogen-activated protein kinase kinase 6, a selective p38 MAPK activator, enhances the ability of the nuclear form of ATF6 to transactivate the grp78 promoter. Our results provide direct evidence that different ER stress inducers use diverse pathways to activate grp78 and that in addition to activation by proteolytic cleavage, ATF6 undergoes specific ER stress-induced phosphorylation. We propose that phosphorylation of ATF6 is a novel mechanism for augmenting its potential as a transcription activator.

scholarly journals Activation of a Novel Transcription Factor through Phosphorylation by WIPK, a Wound-Induced Mitogen-Activated Protein Kinase in Tobacco Plants

2005 ◽  
Vol 139 (1) ◽  
pp. 127-137 ◽  
Author(s):  
Yun-Kiam Yap ◽  
Yutaka Kodama ◽  
Frank Waller ◽  
Kwi Mi Chung ◽  
Hirokazu Ueda ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Tobacco Plants ◽  
Mitogen Activated Protein

scholarly journals MicroRNA-132 Plays an Independent Prognostic Role in Pancreatic Ductal Adenocarcinoma and Acts as a Tumor Suppressor

2019 ◽  
Vol 18 ◽  
pp. 153303381882431 ◽  
Author(s):  
Yan Chen ◽  
Huiyun Zhu ◽  
Yuqiong Wang ◽  
Yingxiao Song ◽  
Pingping Zhang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Prognostic Factor ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Lines ◽  
Mitogen Activated Protein Kinase ◽  
Ductal Adenocarcinoma ◽  
Adenocarcinoma Cell ◽  
Nuclear Transcription Factor ◽  
Mitogen Activated Protein

The role of microRNA-132 in human pancreatic ductal adenocarcinomas is still ambiguous. We explored the association between microRNA-132 and pancreatic ductal adenocarcinoma prognosis. The expression of microRNA-132 in 50 pancreatic ductal adenocarcinoma tissue samples and pancreatic ductal adenocarcinoma cell lines was examined, and the association between its expression and pancreatic ductal adenocarcinoma prognosis was assessed. Functional analysis and factors downstream of microRNA-132 were investigated. Kaplan-Meier survival curves showed that high expression of microRNA-132 was a significant prognostic factor for 1-year survival of patients with pancreatic ductal adenocarcinoma ( P = .028). Multivariate analysis for overall survival indicated that high expression of microRNA-132 was an independent prognostic factor for patients with pancreatic ductal adenocarcinoma ( P = .044). Low expression of microRNA-132 was associated with poor prognosis in pancreatic ductal adenocarcinoma. Ectopic expression of microRNA-132 significantly inhibited proliferation and promoted apoptosis of 2 pancreatic ductal adenocarcinoma cell lines. Bioinformatic analysis revealed that microRNA-132 may exert its effects on pancreatic ductal adenocarcinoma through downregulating mitogen-activated protein kinase 3 and nuclear transcription factor Y subunit α. The results of this study further our understanding of the relationship between microRNA-132 and pancreatic ductal adenocarcinoma by showing that microRNA-132 might inhibit the progression of pancreatic ductal adenocarcinoma by regulating mitogen-activated protein kinase and nuclear transcription factor Y subunit alpha.

Synergistic Activation of Mitogen-Activated Protein Kinase by Cyclic AMP and Myeloid Growth Factors Opposes Cyclic AMP’s Growth-Inhibitory Effects

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 537-553 ◽  
Author(s):  
Angel Wai-mun Lee
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Cell Line ◽  
Mapk Pathway ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Erk Activation ◽  
Mitogen Activated Protein ◽  
Erk Activity ◽  
Myeloid Progenitors

Abstract Colony-stimulating factors (CSFs) promote the proliferation, differentiation, commitment, and survival of myeloid progenitors, whereas cyclic AMP (cAMP)-mediated signals frequently induce their growth arrest and apoptosis. The ERK/mitogen-activated protein kinase (MAPK) pathway is a target for both CSFs and cAMP. We investigated how costimulation by cAMP and colony-stimulating factor-1 (CSF-1) or interleukin-3 (IL-3) modulates MAPK in the myeloid progenitor cell line, 32D. cAMP dramatically increased ERK activity in the presence of CSF-1 or IL-3. IL-3 also synergized with cAMP to activate ERK in another myeloid cell line, FDC-P1. The increase in ERK activity was transmitted to a downstream target, p90rsk. cAMP treatment of 32D cells transfected with oncogenic Ras was found to recapitulate the superactivation of ERK seen with cAMP and CSF-1 or IL-3. ERK activation in the presence of cAMP did not appear to involve any of the Raf isoforms and was blocked by expression of dominant-negative MEK1 or treatment with a MEK inhibitor, PD98059. Although cAMP had an overall inhibitory effect on CSF-1–mediated proliferation and survival, the inhibition was markedly increased if ERK activation was blocked by PD98059. These findings suggest that upregulation of the ERK pathway is one mechanism induced by CSF-1 and IL-3 to protect myeloid progenitors from the growth-suppressive and apoptosis-inducing effects of cAMP elevations.

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