scholarly journals Heregulin Induces Transcriptional Activation of the Progesterone Receptor by a Mechanism That Requires Functional ErbB-2 and Mitogen-Activated Protein Kinase Activation in Breast Cancer Cells

2003 ◽  
Vol 23 (3) ◽  
pp. 1095-1111 ◽  
Author(s):  
Leticia Labriola ◽  
Mariana Salatino ◽  
Cecilia J. Proietti ◽  
Adalí Pecci ◽  
Omar A. Coso ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptor ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Primary Cultures ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Mobility Shift ◽  
T47d Cells ◽  
Mitogen Activated Protein

ABSTRACT The present study addresses the capacity of heregulin (HRG), a ligand of type I receptor tyrosine kinases, to transactivate the progesterone receptor (PR). For this purpose, we studied, on the one hand, an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in female BALB/c mice and, on the other hand, the human breast cancer cell line T47D. HRG was able to exquisitely regulate biochemical attributes of PR in a way that mimicked PR activation by progestins. Thus, HRG treatment of primary cultures of epithelial cells of the progestin-dependent C4HD murine mammary tumor line and of T47D cells induced a decrease of protein levels of PRA and -B isoforms and the downregulation of progesterone-binding sites. HRG also promoted a significant increase in the percentage of PR localized in the nucleus in both cell types. DNA mobility shift assay revealed that HRG was able to induce PR binding to a progesterone response element (PRE) in C4HD and T47D cells. Transient transfections of C4HD and T47D cells with a plasmid containing a PRE upstream of a chloramphenicol acetyltransferase (CAT) gene demonstrated that HRG promoted a significant increase in CAT activity. In order to assess the molecular mechanisms underlying PR transactivation by HRG, we blocked ErbB-2 expression in C4HD and T47D cells by using antisense oligodeoxynucleotides to ErbB-2 mRNA, which resulted in the abolishment of HRG's capacity to induce PR binding to a PRE, as well as CAT activity in the transient-transfection assays. Although the inhibition of HRG binding to ErbB-3 by an anti-ErbB-3 monoclonal antibody suppressed HRG-induced PR activation, the abolishment of HRG binding to ErbB-4 had no effect on HRG activation of PR. To investigate the role of mitogen-activated protein kinases (MAPKs), we used the selective MEK1/MAPK inhibitor PD98059. Blockage of MAPK activation resulted in complete abrogation of HRG's capacity to induce PR binding to a PRE, as well as CAT activity. Finally, we demonstrate here for the first time that HRG-activated MAPK can phosphorylate both human and mouse PR in vitro.

scholarly journals Stimulation of MAPK-phosphatase 1 gene expression by glucocorticoids occurs through a tethering mechanism involving C/EBP

2008 ◽  
Vol 41 (4) ◽  
pp. 239-249 ◽  
Author(s):  
Krishan Johansson-Haque ◽  
Elanchelian Palanichamy ◽  
Sam Okret
Keyword(s):  
Gene Expression ◽  
Binding Site ◽  
Transcriptional Activation ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mobility Shift ◽  
Mitogen Activated Protein ◽  
Mapk Phosphatase ◽  
Mobility Shift Assay

Glucocorticoids (GCs) are known to inhibit mitogen-activated protein kinase (MAPK) signaling. This has been suggested to involve induced expression of MAPK-phosphatase 1 (DUSP1), which dephosphorylates and inactivates MAPKs. However, the mechanism for the transcriptional activation by GCs of DUSP1 or the identification of a GC-responsive region of the gene has so far not been described. To identify GC receptor (GR) binding to the human DUSP1 promoter in vivo, we used a chromatin immunoprecipitation (ChIP) assay and found GR to bind to a region ∼ −1.4 kb upstream of the transcription start site. Using promoter deletion constructs, we identified a GC-responsive region between position −1266 and −1380 bp of the DUSP1 promoter. However, no direct binding of GR to this GC-responsive region was detected in an electrophoretic mobility shift assay (EMSA). Instead, we identified binding of CCAAT/enhancer-binding protein beta (C/EBPβ) to a region between −1311 and −1304 bp of the DUSP1 promoter by EMSA and ChIP. Furthermore, mutation of the C/EBP binding site resulted in a dramatic loss of GC-inducible reporter gene expression, demonstrating the GC responsiveness of the DUSP1 gene to be located to a binding site for C/EBP in the DUSP1 promoter. Also, given that a GR mutant (GRLS7), incapable of transactivating through GC-responsive elements, still was able to bind to the DUSP1 gene in vivo and induce DUSP1 mRNA expression following treatment with GCs suggests the mode of GC activation to be mediated by a tethering mechanism involving the GR and the DUSP1 promoter-bound C/EBPβ.

scholarly journals Porins from Salmonella enterica Serovar Typhimurium Activate the Transcription Factors Activating Protein 1 and NF-κB through the Raf-1-Mitogen-Activated Protein Kinase Cascade

2002 ◽  
Vol 70 (2) ◽  
pp. 558-568 ◽  
Author(s):  
Massimiliano Galdiero ◽  
Mariateresa Vitiello ◽  
Emma Sanzari ◽  
Marina D’Isanto ◽  
Annalisa Tortora ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Salmonella Enterica ◽  
Molecular Mechanisms ◽  
Specific Inhibitor ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Mobility Shift ◽  
Serovar Typhimurium ◽  
Mitogen Activated Protein ◽  
In Cells

ABSTRACT In this study we examined the ability of Salmonella enterica serovar Typhimurium porins to activate activating protein 1 (AP-1) and nuclear factor κB (NF-κB) through the mitogen-activated protein kinase (MAPK) cascade, and we identified the AP-1-induced protein subunits. Our results demonstrate that these enzymes may participate in cell signaling pathways leading to AP-1 and NF-κB activation following porin stimulation of cells. Raf-1 was phosphorylated in response to the treatment of U937 cells with porins; moreover, the porin-mediated increase in Raf-1 phosphorylation is accompanied by the phosphorylation of MAPK kinase 1/2 (MEK1/2), p38, extracellular-signal-regulated kinase 1/2, and c-Jun N-terminal kinase. We used three different inhibitors of phosphorylation pathways: 2′-amino-3′-methoxyflavone (PD-098059), a selective inhibitor of MEK1 activator and the MAPK cascade; 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), a specific inhibitor of the p38 pathway; and 7β-acetoxy-1α,6β,9α-trihydroxy-8,13-epoxy-labd-14-en-11-one (forskolin), an inhibitor at the level of Raf-1 kinase. PD-098059 pretreatment of cells decreases AP-1 and NF-κB activation by lipopolysaccharide (LPS) but not by porins, and SB203580 pretreatment of cells decreases mainly AP-1 and NF-κB activation by porins; in contrast, forskolin pretreatment of cells does not affect AP-1 and NF-κB activation following either porin or LPS stimulation. Our data suggest that the p38 signaling pathway mainly regulates AP-1 and NF-κB activation in cells treated with S. enterica serovar Typhimurium porins. Antibody electrophoretic mobility shift assays showed that JunD and c-Fos binding is found in cells treated with porins, in cells treated with LPS, and in unstimulated cells. However, by 30 to 60 min of stimulation, a different complex including c-Jun appears in cells treated with porins or LPS, while the Fra-2 subunit is present only after porin stimulation. These data suggest different molecular mechanisms of activation induced by porins or by LPS.

scholarly journals Signaling through mitogen-activated protein kinase and Rac/Rho does not duplicate the effects of activated Ras on skeletal myogenesis.

1997 ◽  
Vol 17 (7) ◽  
pp. 3547-3555 ◽  
Author(s):  
M B Ramocki ◽  
S E Johnson ◽  
M A White ◽  
C L Ashendel ◽  
S F Konieczny ◽  
...  
Keyword(s):  
Map Kinase ◽  
Signaling Pathways ◽  
Transcriptional Activation ◽  
Intracellular Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
Negative Effects ◽  
Intracellular Signaling Pathway ◽  
Helix Loop Helix ◽  
Mitogen Activated Protein

The ability of basic helix-loop-helix muscle regulatory factors (MRFs), such as MyoD, to convert nonmuscle cells to a myogenic lineage is regulated by numerous growth factor and oncoprotein signaling pathways. Previous studies have shown that H-Ras 12V inhibits differentiation to a skeletal muscle lineage by disrupting MRF function via a mechanism that is independent of the dimerization, DNA binding, and inherent transcriptional activation properties of the proteins. To investigate the intracellular signaling pathway(s) that mediates the inhibition of MRF-induced myogenesis by oncogenic Ras, we tested two transformation-defective H-Ras 12V effector domain variants for their ability to alter terminal differentiation. H-Ras 12V,35S retains the ability to activate the Raf/MEK/mitogen-activated protein (MAP) kinase cascade, whereas H-Ras 12V,40C is unable to interact directly with Raf-1 yet still influences other signaling intermediates, including Rac and Rho. Expression of each H-Ras 12V variant in C3H10T1/2 cells abrogates MyoD-induced activation of the complete myogenic program, suggesting that MAP kinase-dependent and -independent Ras signaling pathways individually block myogenesis in this model system. However, additional studies with constitutively activated Rac1 and RhoA proteins revealed no negative effects on MyoD-induced myogenesis. Similarly, treatment of Ras-inhibited myoblasts with the MEK1 inhibitor PD98059 revealed that elevated MAP kinase activity is not a significant contributor to the H-Ras 12V effect. These data suggest that an additional Ras pathway, distinct from the well-characterized MAP kinase and Rac/Rho pathways known to be important for the transforming function of activated Ras, is primarily responsible for the inhibition of myogenesis by H-Ras 12V.

scholarly journals Specific Activation of Mitogen-activated Protein Kinase by Transforming Growth Factor-β Receptors in Lipid Rafts Is Required for Epithelial Cell Plasticity

2009 ◽  
Vol 20 (3) ◽  
pp. 1020-1029 ◽  
Author(s):  
Wei Zuo ◽  
Ye-Guang Chen
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Protein Kinase ◽  
Lipid Rafts ◽  
Transforming Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Coated Pits ◽  
Mapk Activation ◽  
Mitogen Activated Protein

Transforming growth factor (TGF)-β regulates a spectrum of cellular events, including cell proliferation, differentiation, and migration. In addition to the canonical Smad pathway, TGF-β can also activate mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt, and small GTPases in a cell-specific manner. Here, we report that cholesterol depletion interfered with TGF-β–induced epithelial-mesenchymal transition (EMT) and cell migration. This interference is due to impaired activation of MAPK mediated by cholesterol-rich lipid rafts. Cholesterol-depleting agents specifically inhibited TGF-β–induced activation of extracellular signal-regulated kinase (ERK) and p38, but not Smad2/3 or Akt. Activation of ERK or p38 is required for both TGF-β–induced EMT and cell migration, whereas PI3K/Akt is necessary only for TGF-β–promoted cell migration but not for EMT. Although receptor heterocomplexes could be formed in both lipid raft and nonraft membrane compartments in response to TGF-β, receptor localization in lipid rafts, but not in clathrin-coated pits, is important for TGF-β–induced MAPK activation. Requirement of lipid rafts for MAPK activation was further confirmed by specific targeting of the intracellular domain of TGF-β type I receptor to different membrane locations. Together, our findings establish a novel link between cholesterol and EMT and cell migration, that is, cholesterol-rich lipid rafts are required for TGF-β–mediated MAPK activation, an event necessary for TGF-β–directed epithelial plasticity.

scholarly journals Activation of mitogen-activated protein kinase kinase (MKK) 3 and MKK6 by type I interferons. VOLUME 280 (2005) 10001-10010

2006 ◽  
Vol 281 (15) ◽  
pp. 10651
Author(s):  
Yongzhong Li ◽  
Sandeep Batra ◽  
Antonella Sassano ◽  
Beata Majchrzak ◽  
David E. Levy ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Mitogen Activated Protein ◽  
Protein Kinase Kinase

scholarly journals MAP4K2 expression associates with survival in triple negative breast cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtype ◽  
Mitogen Activated Protein Kinase ◽  
Breast Cancer Patients ◽  
Primary Tumors ◽  
Mitogen Activated Protein ◽  
Significant Gene

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of mitogen-activated protein kinase kinase kinase kinase 2, encoded by MAP4K2 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, MAP4K2 expression was correlated with distant metastasis-free survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. MAP4K2 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

scholarly journals Novel Pathways for Targeting Tumor Angiogenesis in Metastatic Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Jordan A. Harry ◽  
Mark L. Ormiston
Keyword(s):  
Breast Cancer ◽  
Tumor Angiogenesis ◽  
Metastatic Breast ◽  
Resistance Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Alternative Pathways ◽  
Mitogen Activated Protein ◽  
Chemokine Ligand ◽  
Bone Morphogenetic Protein 9 ◽  
Cancer Tumor

Breast cancer is the most common cancer affecting women and is the second leading cause of cancer related death worldwide. Angiogenesis, the process of new blood vessel development from pre-existing vasculature, has been implicated in the growth, progression, and metastasis of cancer. Tumor angiogenesis has been explored as a key therapeutic target for decades, as the blockade of this process holds the potential to reduce the oxygen and nutrient supplies that are required for tumor growth. However, many existing anti-angiogenic approaches, such as those targeting Vascular Endothelial Growth Factor, Notch, and Angiopoietin signaling, have been associated with severe side-effects, limited survival advantage, and enhanced cancer regrowth rates. To address these setbacks, alternative pathways involved in the regulation of tumor angiogenesis are being explored, including those involving Bone Morphogenetic Protein-9 signaling, the Sonic Hedgehog pathway, Cyclooxygenase-2, p38-mitogen-activated protein kinase, and Chemokine Ligand 18. This review article will introduce the concept of tumor angiogenesis in the context of breast cancer, followed by an overview of current anti-angiogenic therapies, associated resistance mechanisms and novel therapeutic targets.

Sign in / Sign up

Export Citation Format

Share Document