Pin1 links the activities of c-Abl and p300 in regulating p73 function.
Activation of p73 upon genotoxic treatment triggers apoptosis of tumor cells lacking functional p53 and involves the activities of c-Abl and p300. Here, we demonstrate that conformational changes of p73 catalyzed by the prolyl isomerase Pin1 are crucial in this pathway. Lack of Pin1 reduces p73 stability, hampering its accumulation upon genotoxic stress. Indeed, we show that upon treatment with chemotherapeutic drugs c-Abl enhances the phosphorylation-dependent interaction between Pin1 and p73, and this in turn promotes p73 acetylation by p300. Consistently, the ability of c-Abl and p300 to increase p73 stability and transcriptional activity requires Pin1. As a consequence, Pin1 appears to be essential for activation of the apoptotic response by endogenous p73.
Mantovani
Fiamma
F
Laboratorio Nazionale C.I.B., Area Science Park, Padriciano 99, I-34012 Trieste, Italy.
Piazza
Silvano
S
Gostissa
Monica
M
Strano
Sabrina
S
Zacchi
Paola
P
Mantovani
Roberto
R
Blandino
Giovanni
G
Del Sal
Giannino
G
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005809:Genes, Regulator / Q000187:drug effects / Q000235:genetics; D016147:Genes, Tumor Suppressor; D051548:Histone Acetyltransferases; D006801:Humans; D051379:Mice; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation; D016315:Proto-Oncogene Proteins c-abl / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009687:Nuclear Proteins; D019696:Peptidylprolyl Isomerase; D016315:Proto-Oncogene Proteins c-abl; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; C000606846:PIN1 protein, human; C000606850:Pin1 protein, mouse