Modulation Of Mitogen-activated Protein Kinase Activity Research Articles

Gadd45γ regulates cardiomyocyte death and post-myocardial infarction left ventricular remodelling.

Post-infarction remodelling is accompanied and influenced by perturbations in mitogen-activated protein kinase (MAPK) signalling. The growth arrest and DNA-damage-inducible 45 (Gadd45) proteins are small acidic proteins involved in DNA repair and modulation of MAPK activity. Little is known about the role of Gadd45 in the heart. Here, we explored the potential contribution of Gadd45 gamma (γ) isoform to the acute and late phase of heart failure (HF) after myocardial infarction (MI) and determined the mechanisms underlying Gadd45γ actions. The Gadd45γ isoform is up-regulated in murine cardiomyocytes subjected to simulated ischaemia and in the mouse heart during MI. To mimic the situation observed during MI, we enhanced Gadd45γ content in cardiomyocytes with a single injection of an adeno-associated viral (AAV9) vector encoding Gadd45γ under the cTNT promoter. Gadd45γ overexpression induces cardiomyocyte apoptosis, fibrosis, left ventricular dysfunction, and HF. On the other hand, genetic deletion of Gadd45γ in knockout mice confers resistance to ischaemic injury, at least in part by limiting cardiomyocyte apoptosis. Mechanistically, Gadd45γ activates receptor-interacting protein 1 (RIP1) and caspase-8 in a p38 MAPK-dependent manner to promote cardiomyocyte death. This work is the first to demonstrate that Gadd45γ accumulation during MI promotes the development and persistence of HF by inducing cardiomyocyte apoptosis in a p38 MAPK-dependent manner. We clearly identify Gadd45γ as a therapeutic target in the development of HF.

P38MAPK inhibitor SB203580 sensitizes human SNU-C4 colon cancer cells to exisulind-induced apoptosis

Sulindac sulfone (exisulind), is a promising anticancer agent because of its ability to induce apoptosis in a variety of malignant cell types and its minimal toxicity to normal cells. The induction of apoptosis is thought to account for the growth inhibitory effect of exisulind. The mitogen-activated protein kinase (MAPK) cascade has been implicated in the regulation of apoptosis in response to exisulind. With human SNU-C4 colon cancer cells that were much more resistant to exisulind than other colon cancer cells, in this study, we investigated whether the modulation of MAPK activity by using selective MAPK inhibitors can contribute to sensitizing SNU-C4 cells to exisulind. Exisulind (400 and 600 microM) slightly increased the phosphorylation of pERK1/2 but pretreatment with the pERK1/2 inhibitor PD98059 did not significantly change the apoptotic response of SNU-C4 cells. The same doses of exisulind increased the phosphorylation of p38MAPK, and pretreatment with the p38MAPK inhibitor SB203580 significantly potentiated growth inhibition and apoptosis induced by exisulind in SNU-C4 cells. We further found that apoptosis induced by a combination of exisulind and SB203580 was mediated through caspase activation. Collectively, our findings indicate that selective p38MAPK inhibitors potentiate apoptosis induction by exisulind in SNU-C4 cells. Such combinations may provide a more effective and less toxic strategy for the prevention or treatment of colon cancer.

Regulation of Adipogenesis by a Transcriptional Repressor That Modulates MAPK Activation

Mitogen-activated protein kinase (MAPK) is required for cell growth and cell differentiation. In adipogenesis, MAPK activation opposes the differentiation process. The regulatory mechanisms or the cellular factors that regulate the switch between growth and differentiation in the adipogenic lineage have been largely unelucidated. We show here that AEBP1, a transcriptional repressor that is down-regulated during adipogenesis, complexes and protects MAPK from its specific phosphatase in mammalian cells. We further show evidence that the modulation of MAPK activation by AEBP1 is a biologically relevant process in adipogenesis. Our results suggest that modulation of MAPK activation by the protective effect of AEBP1 may constitute a critical part in the determination between cell growth and differentiation in the adipogenic lineage. The proposed mode of action by which a transcription factor regulates MAPK activation is novel.

The STAT3-independent Signaling Pathway by Glycoprotein 130 in Hepatic Cells

Interleukin (IL)-6 is a major regulator of hepatic acute-phase plasma protein (APP) genes. The membrane-proximal 133-amino acid cytoplasmic domain of glycoprotein (gp) 130, containing one copy of the Box3 motif, is sufficient to transmit a productive signal to endogenous APP genes in rat hepatoma H-35 cells. In contrast, a mutant gp130 domain lacking the Box3 motif activates Janus kinases to a normal level but fails to activate signal transducer and activator of transcription 3 and to up-regulate a number of APP genes, including thiostatin, fibrinogen, hemopexin, and haptoglobin. However, in the absence of Box3, gp130 still stimulates the expression of alpha2-macroglobulin and synergizes with IL-1 to up-regulate alpha1-acid glycoprotein. The Box3 motif is not required for activation of the SH2-containing protein tyrosine phosphatase 2 or the mitogen-activated protein kinase (MAPK), nor is the immediate induction of egr-1 and junB significantly altered. Surprisingly, gp130 without any functional Box3 stimulates prolonged activation of MAPK, leading to an extended period of up-regulation of egr-1 and to an extracellularly regulated kinase-mediated reduction in the IL-6-stimulated production of thiostatin. IL-6 reduces proliferation of H-35 cells through signaling by the Box3. In addition, cells expressing Box3-deficient gp130 showed distinct morphologic changes upon receptor activation. Taken together, these results indicate that Box3-derived and Box3-independent signals cooperate in the control of hepatic APP genes and that Box3 may be involved in the modulation of MAPK activity in gp130 signaling.