Reduced signal transduction through glucocorticoid receptor in Burkitt's lymphoma cell lines.
Signal transduction through the glucocorticoid receptor (GR) was shown to be significantly reduced in Epstein-Barr virus (EBV)-positive group I Burkitt's lymphoma (BL) cell lines compared to human B-lymphocytes immortalized by EBV (LCLs). On the basis of hormone binding assays, nuclear DNA binding activity, and transactivation assays the response was reduced 5- to 10-fold. Direct sequence analysis of the expressed glucocorticoid receptor mRNA in two BL cell lines indicated that the phenotype did not result from mutation of the GR gene. By preparing a high-titer polyclonal antiserum against the t-1 region of the human GR, we further showed that the deficient GR response in BLs is largely reflected in reduced GR steady-state protein levels in BL cells compared to LCLs. However, the level of GR mRNA varies less between the BL cell lines and the LCLs. The Cp promoter of EBV which normally drives expression of the EBNA gene family in EBV-immortalized LCLs contains a functional glucocorticoid response element. Transfection of GR expression constructs to group I BL cells converted the GR response to approximately LCL levels both with respect to hormone binding and glucocorticoid-dependent transcription of a glucocorticoid-dependent promoter. A modest activation of EBNA-2 expression was seen in some such cell lines, suggesting that the lower GR response contributes to the down-regulation of EBNA expression observed in BL.
Sinclair
A J
AJ
Ludwig Institute for Cancer Research, St. Mary's Hospital Medical School, London, United Kingdom.
Jacquemin
M G
MG
Brooks
L
L
Shanahan
F
F
Brimmell
M
M
Rowe
M
M
Farrell
P J
PJ
D000956:Antigens, Viral / Q000096:biosynthesis; D001483:Base Sequence; D001692:Biological Transport / Q000502:physiology; D002051:Burkitt Lymphoma / Q000378:metabolism* / Q000382:microbiology; D002461:Cell Line, Transformed; D004279:DNA, Viral / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D019309:Epstein-Barr Virus Nuclear Antigens; D005814:Genes, Viral / Q000502:physiology; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D007106:Immune Sera; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D011965:Receptors, Glucocorticoid / Q000378:metabolism / Q000502:physiology*; D012045:Regulatory Sequences, Nucleic Acid / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology; D014407:Tumor Cells, Cultured
D000956:Antigens, Viral; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D019309:Epstein-Barr Virus Nuclear Antigens; D007106:Immune Sera; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid