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

• DOI: 10.1073/pnas.1017536108
• Publication Date: 2011-08-10T02:53:29Z
• Authors: Chang-Il Hwang; Andres Matoso; David C. Corney; Andrea Flesken-Ni...; Stefanie Körner; Wei Wang; Carla Boccaccio; Snorri S. Thorgei...; Paolo M. Comoglio; Heiko Hermeking; Alexander Yu. Nik...
• Keywords: 0303 health sciences; Sp1 Transcription Factor; Ovary; Proto-Oncogene Proteins c-met; Epithelium; 3. Good health; Gene Expression Regulation, Neoplastic; Mice; MicroRNAs; 03 medical and health sciences; ovarian cancer; mutant p53; C-MET; Transcriptional Activation; Gene Expression; Down-Regulation; SP1; growth; Mutation; Cell Movement; Cell Line, Tumor; Animals; Humans; Female; Mutant Proteins; Neoplasm Invasiveness; Receptors, Growth Factor; Gene Silencing; Tumor Suppressor Protein p53; Promoter Regions, Genetic; Protein Binding

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