The prolyl isomerase Pin1 affects Che-1 stability in response to apoptotic DNA damage

Francesca De Nicola; Tiziana Bruno; Simona Iezzi; Monica Di Padova; Aristide Floridi; Claudio Passananti; Giannino Del Sal; Maurizio Fanciulli

doi:10.1074/jbc.M610282200

The prolyl isomerase Pin1 affects Che-1 stability in response to apoptotic DNA damage

J Biol Chem. 2007 Jul 6;282(27):19685-91. doi: 10.1074/jbc.M610282200. Epub 2007 Apr 27.

Authors

Francesca De Nicola¹, Tiziana Bruno, Simona Iezzi, Monica Di Padova, Aristide Floridi, Claudio Passananti, Giannino Del Sal, Maurizio Fanciulli

Affiliation

¹ Laboratory B, Experimental Research Center and Rome Oncogenomic Center, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy.

PMID: 17468107
DOI: 10.1074/jbc.M610282200

Abstract

We have previously demonstrated that DNA damage leads to stabilization and accumulation of Che-1, an RNA polymerase II-binding protein that plays an important role in transcriptional activation of p53 and in maintenance of the G(2)/M checkpoint. Here we show that Che-1 is down-regulated during the apoptotic process. We found that the E3 ligase HMD2 physically and functionally interacts with Che-1 and promotes its degradation via the ubiquitin-dependent proteasomal system. Furthermore, we found that in response to apoptotic stimuli Che-1 interacts with the peptidyl-prolyl isomerase Pin1 and that conformational changes generated by Pin1 are required for Che-1/HDM2 interaction. Notably, a Che-1 mutant lacking the capacity to bind Pin1 exhibits an increased half-life and this correlates with a diminished apoptosis in response to genotoxic stress. Our results establish Che-1 as a new Pin1 and HDM2 target and confirm its important role in the cellular response to DNA damage.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism*
Apoptosis*
Cell Division
Cell Line, Tumor
DNA Damage*
Down-Regulation
G2 Phase
Humans
Mice
Mutation
NIMA-Interacting Peptidylprolyl Isomerase
Peptidylprolyl Isomerase / genetics
Peptidylprolyl Isomerase / metabolism*
Proteasome Endopeptidase Complex / genetics
Proteasome Endopeptidase Complex / metabolism
Proto-Oncogene Proteins c-mdm2 / genetics
Proto-Oncogene Proteins c-mdm2 / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Transcription Factors / genetics
Transcription Factors / metabolism*
Ubiquitin / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism

Substances

AATF protein, human
Apoptosis Regulatory Proteins
NIMA-Interacting Peptidylprolyl Isomerase
Repressor Proteins
Transcription Factors
Ubiquitin
MDM2 protein, human
Mdm2 protein, mouse
Proto-Oncogene Proteins c-mdm2
Ubiquitin-Protein Ligases
Proteasome Endopeptidase Complex
PIN1 protein, human
Peptidylprolyl Isomerase
Pin1 protein, mouse