Evidence That Inhibition of p44/42 Mitogen-activated Protein Kinase Signaling Is a Factor in Proteasome Inhibitor-mediated Apoptosis
| Autor: | George W. Small, Yue Y. Shi, Robert Z. Orlowski |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2002 |
| Předmět: |
MAPK/ERK pathway
Proteasome Endopeptidase Complex MAP Kinase Signaling System Lactacystin Apoptosis Breast Neoplasms Cysteine Proteinase Inhibitors Biochemistry chemistry.chemical_compound Epidermal growth factor Multienzyme Complexes Nitriles medicine Butadienes Tumor Cells Cultured Chymotrypsin Humans Enzyme Inhibitors Protein kinase A Molecular Biology Flavonoids Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 biology Chemistry Cell Biology Cell biology Cysteine Endopeptidases Kinetics Proteasome Mitogen-activated protein kinase Cancer research Proteasome inhibitor biology.protein Dactinomycin Phosphorylation Female Mitogen-Activated Protein Kinases Oligopeptides medicine.drug |
| DOI: | 10.17615/v6v3-f557 |
| Popis: | The proteasome is emerging as a target for cancer therapy because small molecule inhibitors of its catalytic activity induce apoptosis in both in vitro and in vivo models of human malignancies and are proving to have efficacy in early clinical trials. To further elucidate the mechanism of action of these inhibitors, their impact on signaling through the p44/42 mitogen-activated protein kinase (MAPK) pathway was studied. Proteasome inhibition with either carbobenzoxy-leucyl-leucyl-phenylalaninal or lactacystin led to a loss of dually phosphorylated, activated p44/42 MAPK in A1N4-myc human mammary and MDA-MB-231 breast carcinoma cells in a dose- and time-dependent fashion. This correlated with an induction of the dual specificity MAPK phosphatases (MKP)-1 and -2, and blockade of MKP induction using either actinomycin D or Ro-31-8220 significantly decreased loss of activated p44/42 MAPK. Inhibition of p44/42 MAPK signaling by use of the MAPK kinase inhibitors PD 98059 or U0126, or by use of a dominant negative MAPK construct, enhanced proteasome inhibitor-mediated apoptosis. Conversely, activation of MAPK by epidermal growth factor, or use of a mutant MAPK resistant to MKP-mediated dephosphorylation, inhibited apoptosis. These studies support a role for inactivation of signaling through the p44/42 MAPK pathway in proteasome inhibitor-mediated apoptosis. |
| Databáze: | OpenAIRE |
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