The prolyl cis/trans isomerase cyclophilin 18 interacts with the tumor suppressor p53 and modifies its functions in cell cycle regulation and apoptosis.
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.
Baum
N
N
Department of Biochemistry, Leibniz-Institute for Age Research (Fritz Lipmann Institute), Jena, Germany.
Schiene-Fischer
C
C
Frost
M
M
Schumann
M
M
Sabapathy
K
K
Ohlenschläger
O
O
Grosse
F
F
Schlott
B
B
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*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D021983:Cyclophilins