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 peptidylprolyl 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.

Modelling the molecular mechanism of protein–protein interactions and their inhibition: CypD–p53 case study

“…2). This is in accordance with a previous study, which reported that p53 binds at the CsA-binding site of the cyclophilin protein, Cyp18 [60]. It can be deduced that this might be the reason behind the inhibition of CypD-p53 interaction by CsA.…”

Profilin-1 Overexpression in MDA-MB-231 Breast Cancer Cells Is Associated with Alterations in Proteomics Biomarkers of Cell Proliferation, Survival, and Motility as Revealed by Global Proteomics Analyses

“…In cancer, it has been suggested that PPIA regulation is controlled by p53 or by the hypoxia inducible factor (HIF)-1a. A causative relationship resulting from the direct interaction between PPIA and p53, has been shown during apoptosis and cell cycle regulation (Baum et al, 2009). P53 is known to interact with several proteins involved in cell proliferation; cell proliferation regulation and cell death regulation, some of which have been identified in this study (see Table 2 for reported evidence of their roles).…”

Insights into Immunophilin Structure and Function

“…In various cancers, CypA is directly under the transcriptional control of two critical transcription factors for cancer development: the hypoxia-inducible factor 1 alpha subunit (HIF-1 ) [237] and the tumor suppressor p53 [238]. Moreover, a physical and functional interaction between p53 and CypA was identified to mediate the anti-apoptotic effect of CypA [239]. The cyclophilin inhibitors CsA and sanglifehrin A each can synergistically increase apoptotic cell death in hepatocellular carcinoma cells when combined with cisplatin.…”