title: P73 tumor suppressor and its targets, p21 and PUMA, are required for madin-darby canine kidney cell morphogenesis by maintaining an appropriate level of epithelial to mesenchymal transition.
abstract: P73, a member of p53 tumor suppressor family, plays a crucial role in tumor suppression and neural development. Due to the usage of two promoters, p73 is expressed as two isoforms, TAp73 and âNp73, with opposing functions. Here, we investigated the potential role of p73 in epithelial polarity and morphogenesis by using Madin-Darby canine kidney (MDCK) cells as a model system. We found that knockdown of TAp73 enhances, whereas knockdown of âNp73 inhibits, MDCK cell proliferation and migration in two-dimensional (2-D) culture. We also found that knockdown of TAp73, but not âNp73, disrupts cyst formation of MDCK cells in three-dimensional (3-D) culture. Interestingly, we found that p21 and PUMA, both of which are induced by TAp73 but repressed by âNp73, are required for suppressing cell proliferation and migration in 2-D culture and for MDCK ce ll morphogenesis in 3-D culture. Finally, we showed knockdown of TAp73, p21 or PUMA induces epithelial to mesenchymal transition (EMT) with a decrease in E-cadherin and an increase in EMT transcription factors. Together, our data suggest that TAp73, p21 and PUMA play a critical role in modulating MDCK cell morphogenesis by maintaining an appropriate level of the EMT.
authors.affiliation: Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of Californian at Davis, Davis, CA, USA.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of Californian at Davis, Davis, CA, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Young
authors.affiliation: Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of Californian at Davis, Davis, CA, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of Californian at Davis, Davis, CA, USA.
authors.forename: Xinbin
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004285:Dogs; D058750:Epithelial-Mesenchymal Transition; D007668:Kidney / Q000166:cytology* / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D009687:Nuclear Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D020741:rho GTP-Binding Proteins
keywords: MDCK; P73; PUMA; epithelial-to-mesenchymal transition (EMT); p21