Rac1-MKK3-p38-MAPKAPK2 Pathway Promotes Urokinase Plasminogen Activator mRNA Stability in Invasive Breast Cancer Cells
| Autor: | Qiwei Han, Dafang Bian, Chitladda Mahanivong, Jay Leng, Jiahuai Han, Shuang Huang, Zhixing K. Pan, Kevin A. Carpenter |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
rac1 GTP-Binding Protein
MAPK/ERK pathway Cell signaling MAP Kinase Kinase 3 p38 mitogen-activated protein kinases Receptor expression Breast Neoplasms Protein Serine-Threonine Kinases p38 Mitogen-Activated Protein Kinases Biochemistry Tumor Cells Cultured Humans Neoplasm Invasiveness RNA Messenger Protein kinase A 3' Untranslated Regions Molecular Biology DNA Primers Mitogen-Activated Protein Kinase Kinases Base Sequence biology MAPKAPK2 Intracellular Signaling Peptides and Proteins Cell Biology Protein-Tyrosine Kinases Urokinase-Type Plasminogen Activator Up-Regulation biology.protein Cancer research Vitronectin Mitogen-Activated Protein Kinases Signal transduction |
| Zdroj: | Journal of Biological Chemistry. 277:48379-48385 |
| ISSN: | 0021-9258 |
| Popis: | We reported previously that down-regulating or functionally blocking alphav integrins inhibits endogenous p38 mitogen-activated protein kinase (MAPK) activity and urokinase plasminogen activator (uPA) expression in invasive MDA-MB-231 breast cancer cells whereas engaging alphav integrins with vitronectin activates p38 MAPK and up-regulates uPA expression (Chen, J., Baskerville, C., Han, Q., Pan, Z., and Huang, S. (2001) J. Biol. Chem. 276, 47901-47905). Currently, it is not clear what upstream and downstream signaling molecules of p38 MAPK mediate alphav integrin-mediated uPA up-regulation. In the present study, we found that alphav integrin ligation activated small GTPase Rac1 preferentially, and dominant negative Rac1 inhibited alphav integrin-mediated p38 MAPK activation. Using constitutively active MAPK kinases, we found that both constitutively active MKK3 and MKK6 mutants were able to activate p38 MAPK and up-regulate uPA expression, but only dominant negative MKK3 blocked alphav integrin-mediated p38 MAPK activation and uPA up-regulation. These results suggest that MKK3, rather than MKK6, mediates alphav integrin-induced p38 MAPK activation. Among the potential downstream effectors of p38 MAPK, we found that only MAPK-activated protein kinase 2 affects alphav integrin-mediated uPA up-regulation significantly. Finally, using beta-globin reporter gene constructs containing uPA mRNA 3'-untranslated region (UTR) and adenosine/uridine-rich elements-deleted 3'-UTR, we demonstrated that p38 MAPK/MAPK-activated protein kinase 2 signaling pathway regulated uPA mRNA stability through a mechanism involving the adenosine/uridine-rich elements sequence in 3'-UTR of uPA mRNA. |
| Databáze: | OpenAIRE |
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