Knocking down PML impairs p53 signaling transduction pathway and suppresses irradiation induced apoptosis in breast carcinoma cell MCF-7.
The promyelocytic leukemia (PML) can selectively and dynamically recruit a number of proteins including p53 to form a sub-nuclear multiprotein chamber named PML-NBs. In DNA damage response, p53 is recruited into PML-NBs and modified by phosphorylations and acetylations, which in turn potentiate its transcriptional and pro-apoptotic activities. In contrast, in ... carcinoma cells, the role of PML in the irradiation induced p53-mediated apoptosis is not precisely understood. In this study, we have used the breast carcinoma cell line, MCF-7, and stably suppressed the expression of PML. Inhibition of PML expression had no detectable effect on the expression of endogenous p53 at the mRNA level; however, a significant decrease of p53 protein was observed. There was also an increase in the p53-MDM2 complexes, which may facilitate p53 protein degradation by the ubiquitin-proteasome pathway, also in irradiation treated cells. The p53 transcriptional activity was attenuated both in unstressed and 10 Gy irradiation treated cells. Moreover, inhibition of PML expression in MCF-7 cells significantly reduced p53 downstream genes, cell cycle arrest gene p21(WAF/cip-1) and pro-apoptotic gene Bax expression, then irradiation-induced apoptosis. These results suggest that PML is a key regulator in the irradiation activated p53 apoptotic pathway in breast carcinoma cells.
Mesh Terms:
Apoptosis, Breast Neoplasms, Cobalt Radioisotopes, Cyclin-Dependent Kinase Inhibitor p21, Down-Regulation, Female, Flow Cytometry, Gene Expression Regulation, Neoplastic, Humans, Luciferases, Neoplasm Proteins, Nuclear Proteins, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-mdm2, RNA, Messenger, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transcription Factors, Transcription, Genetic, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Ubiquitin, bcl-2-Associated X Protein
Apoptosis, Breast Neoplasms, Cobalt Radioisotopes, Cyclin-Dependent Kinase Inhibitor p21, Down-Regulation, Female, Flow Cytometry, Gene Expression Regulation, Neoplastic, Humans, Luciferases, Neoplasm Proteins, Nuclear Proteins, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-mdm2, RNA, Messenger, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transcription Factors, Transcription, Genetic, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Ubiquitin, bcl-2-Associated X Protein
J. Cell. Biochem.
Date: Feb. 15, 2006
PubMed ID: 16215989
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