title: S100A4 interacts with p53 in the nucleus and promotes p53 degradation.
abstract: S100A4 is a small calcium-binding protein that is commonly overexpressed in a range of different tumor types, and it is widely accepted that S100A4 has an important role in the process of cancer metastasis. In vitro binding assays has shown that S100A4 interacts with the tumor suppressor protein p53, indicating that S100A4 may have additional roles in tumor development. In the present study, we show that endogenous S100A4 and p53 interact in complex samples, and that the interaction increases after inhibition of MDM2-dependent p53 degradation using Nutlin-3A. Further, using proximity ligation assay, we show that the interaction takes place in the cell nucleus. S100A4 knockdown experiments in two p53 wild-type cell lines, A549 and HeLa, resulted in stabilization of p53 protein, indicating that S100A4 is promoting p53 degradation. Finally, we demonstrate that S100A4 knockdown leads to p53-dependent cell cycle arrest and increased cisplatin-induced apoptosis. Thus, our data add a new layer to the oncogenic properties of S100A4 through its inhibition of p53-dependent processes.
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden.
authors.forename: L M
authors.initials: LM
authors.lastname: Orre
authors.forename: E
authors.initials: E
authors.lastname: Panizza
authors.forename: V O
authors.initials: VO
authors.lastname: Kaminskyy
authors.forename: E
authors.initials: E
authors.lastname: Vernet
authors.forename: T
authors.initials: T
authors.lastname: Gräslund
authors.forename: B
authors.initials: B
authors.lastname: Zhivotovsky
authors.forename: J
authors.initials: J
authors.lastname: Lehtiö
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D010879:Piperazines; D034741:RNA, Small Interfering; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D016159:Tumor Suppressor Protein p53; C077591:S100A4 protein, human; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D053148:Caspase 3; D002945:Cisplatin