targeted inactivation of snail family emt regulatory factors by a co(iii)-ebox conjugate有针对性的失活蜗牛家庭emt监管因素的公司(iii)上述共轭.pdfVIP

Targeted Inactivation of Snail Family EMT Regulatory Factors by a Co(III)-Ebox Conjugate Allison S. Harney1,2, Thomas J. Meade1,2,3, Carole LaBonne1,3* 1 Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America, 2 Departments of Chemistry, Neurobiology, and Radiology, Northwestern University, Evanston, Illinois, United States of America, 3 Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, Illinois, United States of America Abstract Snail family proteins are core EMT (epithelial-mesenchymal transition) regulatory factors that play essential roles in both development and disease processes and have been associated with metastasis in carcinomas. Snail factors are required for the formation of neural crest stem cells in most vertebrate embryos, as well as for the migratory invasive behavior of these cells. Snail factors have recently been linked to the formation of cancer stem cells, and expression of Snail proteins may be associated with tumor recurrence and resistance to chemotherapy and radiotherapy. We report that Co(III)-Ebox is a potent inhibitor of Snail- mediated transcriptional repression in breast cancer cells and in the neural crest of Xenopus. We further show that the activity of Co(III)-Ebox can be modulated by temperature, increasing the utility of this conjugate as a Snail inhibitor in model organisms. We exploit this feature to further delineate the requirements for Snail function during neural crest development, showing that in addition to the roles that Snail factors play in neural crest precursor formation and neural crest EMT/migration, inhibition of Snail function after the onset of neural crest migration leads to a loss of neural crest derived melanocytes. Co(III)-Ebox-mediated inhibition therefore provides a powerful tool for analysing the function of these core EMT facto