title: The prolyl cis/trans isomerase cyclophilin 18 interacts with the tumor suppressor p53 and modifies its functions in cell cycle regulation and apoptosis.
abstract: The functional diversity of the tumor suppressor protein p53 is mainly regulated by protein interactions. In this study, we describe a new interaction with the peptidyl-prolyl cis/trans isomerase cyclophilin 18 (Cyp18). The interaction reduced the sequence-specific DNA binding of p53 in vitro, whereas the inhibition of the interaction increased p53-reporter gene activity in vivo. The active site of the folding helper enzyme Cyp18 was directly involved in binding. The proline-rich region (amino acids 64-91) of p53 was most likely responsible for the observed binding because a synthetic peptide comprising amino acids 68-81 of p53 inhibited this interaction, and a p53 variant containing a proline residue at position 72 (p53(P72)) interacted with Cyp18 more effectively than the corresponding p53(R72) variant. Impairment of the Cyp18-p53 interaction induced an accumulation of cells in the G2/M phase of the cell cycle, which was more pronounced when p53(P72) was expressed compared with p53(R72) in an otherwise isogenic cellular background. Moreover, p53-dependent apoptosis was elevated in Cyp18 knockout cells, suggesting an antiapoptotic potential of Cyp18-p53 complexes. Functional in vivo data hint to a possible clinical relevance of the p53-Cyp18 interaction observed.
authors.affiliation: Department of Biochemistry, Leibniz-Institute for Age Research (Fritz Lipmann Institute), Jena, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Baum
authors.forename: C
authors.initials: C
authors.lastname: Schiene-Fischer
authors.forename: M
authors.initials: M
authors.lastname: Frost
authors.forename: M
authors.initials: M
authors.lastname: Schumann
authors.forename: K
authors.initials: K
authors.lastname: Sabapathy
authors.forename: O
authors.initials: O
authors.lastname: Ohlenschläger
authors.forename: F
authors.initials: F
authors.lastname: Grosse
authors.forename: B
authors.initials: B
authors.lastname: Schlott
mesh_terms: D019943:Amino Acid Substitution; D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism*; D016195:G2 Phase / Q000502:physiology*; D006801:Humans; D020125:Mutation, Missense; D011485:Protein Binding / Q000502:physiology; D017510:Protein Folding; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D021983:Cyclophilins