Dysregulation of platelet-derived growth factor beta-receptor expression by DeltaNp73 in neuroblastoma.
We have previously characterized how p53 family proteins control the transcriptional regulation of the platelet-derived growth factor beta-receptor (PDGFRB) and found that DeltaNp73alpha, acting dominant-negatively to p53 and p73, can upregulate PDGFRB promoter activity. Here, we report that PDGFRB regulation differs between two neuroblastoma cell lines, correlating with the actions of DeltaNp73. We found that PDGFRB was highly expressed in IMR-32 cells, and serum stimulation of IMR-32 cells did not downregulate PDGFRB expression, as seen in SH-SY5Y cells. In IMR-32, DeltaNp73 was found constitutively bound to the PDGFRB promoter, and silencing of DeltaNp73 resulted in repression of PDGFRB promoter activity as well as decreased PDGFRB protein expression. However, the anticancer drug cisplatin, known to stabilize and activate p53 and p73, downregulated PDGFRB expression not only in SH-SY5Y but also in IMR-32. Chromatin immunoprecipitation showed that cisplatin removed DeltaNp73 from the PDGFRB promoter and recruited p53 and p73, leading to binding of histone deacetylase 4. These results suggest a direct role of DeltaNp73 in the constantly enhanced PDGFRB expression seen in tumors.
Wetterskog
Daniel
D
Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
Moshiri
Abtin
A
Ozaki
Toshinori
T
Uramoto
Hidetaka
H
Nakagawara
Akira
A
Funa
Keiko
K
D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D009447:Neuroblastoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D044967:Serum; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; D020797:Receptor, Platelet-Derived Growth Factor beta; C400300:HDAC4 protein, human; D006655:Histone Deacetylases; D002945:Cisplatin