16-kDa prolactin down-regulates inducible nitric oxide synthase expression through inhibition of the signal transducer and activator of transcription 1/IFN regulatory factor-1 pathway
| Autor: | Li Yuan Yu-Lee, Florence L. Lee, Sue Hwa Lin, Jeri Kim, Tuhina Mazumdar, Matthew Galfione, Albert K. Liang, N. Tony Eissa, Cynthia Lee, Michiya Nishino, Sok Hyong Lee, Lili Feng, Gabriela Garcia |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
MAPK/ERK pathway
Cancer Research Angiogenesis MAP Kinase Signaling System Down-Regulation Nitric Oxide Synthase Type II Nitric Oxide p38 Mitogen-Activated Protein Kinases Animals STAT1 Phosphorylation biology Activator (genetics) NF-kappa B Endothelial Cells Phosphoproteins Peptide Fragments Prolactin Rats Nitric oxide synthase DNA-Binding Proteins STAT1 Transcription Factor Oncology biology.protein Cancer research STAT protein Trans-Activators Signal transduction Nitric Oxide Synthase Interferon Regulatory Factor-1 Interleukin-1 |
| Zdroj: | Cancer research. 65(17) |
| ISSN: | 0008-5472 |
| Popis: | Angiogenesis plays a key role in promoting tumorigenesis and metastasis. Several antiangiogenic factors have been shown to inhibit tumor growth in animal models. Understanding their mechanism of action would allow for better therapeutic application. 16-kDa prolactin (PRL), a NH2-terminal natural breakdown fragment of the intact 23-kDa PRL, exerts potent antiangiogenic and antitumor activities. The signaling mechanism involved in 16-kDa PRL action in endothelial cells remains unclear. One of the actions of 16-kDa PRL is to attenuate the production of nitric oxide (NO) through the inhibition of inducible NO synthase (iNOS) expression in endothelial cells. To delineate the signaling mechanism from 16-kDa PRL, we examined the effect of 16-kDa PRL on interleukin IL-1β–inducible iNOS expression, which is regulated by two parallel pathways, one involving IFN regulatory factor 1 (IRF-1) and the other nuclear factor-κB (NF-κB). Our studies showed that 16-kDa PRL specifically blocked IRF-1 but not NF-κB signaling to the iNOS promoter. We found that IL-1β regulated IRF-1 gene expression through stimulation of p38 mitogen-activated protein kinase (MAPK), which mediated signal transducer and activator of transcription 1 (Stat1) serine phosphorylation and Stat1 nuclear translocation to activate the IRF-1 promoter. 16-kDa PRL effectively inhibited IL-1β–inducible p38 MAPK phosphorylation, resulting in blocking Stat1 serine phosphorylation, its subsequent nuclear translocation and activation of the Stat1 target gene IRF-1. Thus, 16-kDa PRL inhibits the p38 MAPK/Stat1/IRF-1 pathway to attenuate iNOS/NO production in endothelial cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|