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P38 Mitogen-Activated Protein Kinase in Metastasis Associated With Transforming Growth Factor Beta

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Annual rept. 15 May 2004-14 May 2005

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Metastatic mammary tumor cells frequently express high levels of the transforming growth factor Beta TGF-BETA. Although TGF-beta is a potent tumor suppressor, it can promote formation of highly metastatic tumors by stimulating an epithelial to mesenchymal transition EMT, migration, invasion, and changes in tumor microenvironment. The molecular mechanisms of EMT, cell migration and invasion induced by TGFbeta are not well understood. We found that inhibition of the p38 mitogen activated protein kinase p38 MAPK pathway blocked TGFbeta-induced EMT in NMuMG mammary epithelial cells 1. Inhibitors of p38 MAPK also blocked migration of MDA-MB-23l and 4T1 metastatic carcinoma cells 1. These results suggest a critical role for p38 MAPK signaling in the tumor promoting activity of TGF-beta. In addition, recent studies suggest that the p38 MAPK signaling pathway is important for the invasive phenotype of carcinoma cells by contributing in the activity of matrix proteases 2, 3. Thus, the p38 MAPK pathway is a potential target for selective therapeutic intervention. The purpose of this research is 1 to examine in vitro the role of the p38 MAPK pathway in tumor cell motility and invasiveness, and 2 to evaluate the role of p38 MAPK in tumor growth and metastasis in vivo. To study the contribution of TGFbeta-p38MAPK signaling in metastasis, we have used metastatic breast cancer MDA-MB-23 1 cell line. These cells were genetically modified to express kinase mutants of the TGF-beta type I receptor TbetaRI, Alk5.

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  • Biochemistry
  • Anatomy and Physiology

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