Alternative pathway of transcriptional induction of p21WAF1/Cip1 by cyclosporine A in p53-deficient human glioblastoma cells.
The cyclin-dependent kinase inhibitor p21WAF1/CIP1, a critical regulator of the cell cycle, is mainly regulated by p53 tumour suppressor at the transcriptional level. Restoration of p21WAF1/Cip1 expression in p53-deficient malignant cells suppress tumour growth. Cyclosporine A (CsA) affects proliferation and survival of cultured malignant glioma cells and impairs growth of experimental gliomas. CsA induced p21WAF1/Cip1 expression de novo in human glioblastoma cells with p53 deficiency. We demonstrate that transcriptional activation of p21WAF1/Cip1 expression correlated with induction of ERK1/2 and c-Jun phosphorylation in CsA-treated glioblastoma cells. Pre-treatment with ERK pathway inhibitors or overexpression of dominant-negative mutants MKK1, ERK2 and c-Jun reduced activation of the p21WAF1/Cip1 promoter. Overexpression of tethered AP-1 dimers containing c-Jun was sufficient to activate the truncated -200 bp p21WAF1/Cip1 promoter, which does not contain p53 binding sites. Chromatin immunoprecipitation revealed that P-c-Jun is bound to the proximal part of p21WAF1/Cip1 promoter in CsA-treated glioblastoma cells. It suggests that CsA activates p53-independent, transcriptional activation p21WAF1/Cip1 expression, mediated by ERK/c-Jun/AP-1 signaling pathway.
Zupanska
Agata
A
Laboratory of Transcription Regulation, Department Cell Biology, Nencki Institute of Experimental Biology, 3 Pasteur Str., 02-093, Warsaw, Poland.
Adach
Alicja
A
Dziembowska
Magdalena
M
Kaminska
Bozena
B
D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D019281:Dimerization; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D050759:Cyclin-Dependent Kinase Inhibitor p21; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D016572:Cyclosporine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3