Autocrine interleukin-6 production in renal cell carcinoma: evidence for the involvement of p53.
Interleukin (IL)-6 is an autocrine growth factor for renal cell carcinoma (RCC). We sought to determine whether p53 regulates constitutive IL-6 production. RCC cell lines containing mutant (mut) p53 produced higher levels of IL-6 than those containing wild-type (wt) p53 (P < 0.05). Transfection of wt p53 into RCC cell lines bearing mut p53 (UOK 121LN) or wt p53 (A498 and ACHN) resulted in repression of IL-6 promoter chloramphenicol acetyltransferase activity (P < 0.05). Mutant p53 was either less effective at repressing IL-6 promoter activity (ACHN cells) or enhanced IL-6 promoter activity (A498 cells). A498 cells stably transfected with mut p53 produced higher levels of IL-6 than A498 cells transfected with an empty expression vector (P < 0.05). Electrophoretic mobility shift assays showed decreased binding of CAAT enhancer binding protein, cyclic AMP responsive element binding protein, +/- nuclear factor-kappaB transcription factors to the IL-6 promoter in various RCC cell lines transfected with wt p53 (P < 0.05) but not in those transfected with mut p53. These data suggest that: (a) mutation of p53 contributes to the overexpression of IL-6 in RCC; and (b) wt p53 represses IL-6 expression, at least in part, by interfering with specific transcription factor binding to the IL-6 promoter.
Angelo
Laura S
LS
Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Talpaz
Moshe
M
Kurzrock
Razelle
R
D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D015850:Interleukin-6; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53