Wild-type p53 controls cell motility and invasion by dual regulation of MET expression

Chang Il Hwang, Andres Matoso, David C. Corney, Andrea Flesken-Nikitin, Stefanie Körner, Wei Wang, Carla Boccaccio, Snorri S. Thorgeirsson, Paolo M. Comoglio, Heiko Hermeking, Alexander Yu Nikitin

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Abstract

Recent observations suggest that p53 mutations are responsible not only for growth of primary tumors but also for their dissemination. However, mechanisms involved in p53-mediated control of cell motility and invasion remain poorly understood. By using the primary ovarian surface epithelium cell culture, we show that conditional inactivation of p53 or expression of its mutant forms results in overexpression of MET receptor tyrosine kinase, a crucial regulator of invasive growth. At the same time, cells acquire increased MET-dependent motility and invasion. Wild-type p53 negatively regulates MET expression by two mechanisms: (i) transactivation of MET-targeting miR-34, and (ii) inhibition of SP1 binding to MET promoter. Both mechanisms are not functional in p53 absence, but mutant p53 proteins retain partial MET promoter suppression. Accordingly, MET overexpression, cell motility, and invasion are particularly high in p53-null cells. These results identify MET as a critical effector of p53 and suggest that inhibition of MET may be an effective antimetastatic approach to treat cancers with p53 mutations. These results also show that the extent of advanced cancer traits, such as invasion, may be determined by alterations in individual components of p53/MET regulatory network.

Original languageEnglish (US)
Pages (from-to)14240-14245
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number34
DOIs
StatePublished - Aug 23 2011
Externally publishedYes

ASJC Scopus subject areas

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    Hwang, C. I., Matoso, A., Corney, D. C., Flesken-Nikitin, A., Körner, S., Wang, W., Boccaccio, C., Thorgeirsson, S. S., Comoglio, P. M., Hermeking, H., & Nikitin, A. Y. (2011). Wild-type p53 controls cell motility and invasion by dual regulation of MET expression. Proceedings of the National Academy of Sciences of the United States of America, 108(34), 14240-14245. https://doi.org/10.1073/pnas.1017536108