Schouten G J, van der Eb A J, Zantema A
Laboratory for Molecular Carcinogenesis, Sylvius Laboratories, University of Leiden, The Netherlands.
EMBO J. 1995 Apr 3;14(7):1498-507. doi: 10.1002/j.1460-2075.1995.tb07136.x.
We have previously demonstrated that expression of major histocompatibility complex (MHC) class I genes is repressed in baby rat kidney cells transformed by early region 1 of oncogenic adenovirus type 12 (Ad12E1). Reduced expression of MHC class I antigens contributes to the escape of Ad12-transformed cells from T-cell-mediated immune surveillance and to tumour induction. In this study, we show that repression of MHC class I expression by Ad12E1A is mediated via the H2TF1 element of the MHC class I promoter. This element binds NF kappa B and KBF1, two factors which play a major role in the regulation of MHC class I expression in vivo. In extracts from Ad12E1-transformed cells, binding of KBF1 and NF kappa B to the H2TF1 element is decreased. This is caused by reduced production of p50-NF kappa B1, the 50 kDa subunit shared by KBF1 and NF kappa B, due to interference with p105-NF kappa B1 processing by Ad12-13S-E1A protein. Overexpression of the p105-NF kappa B1 cDNA, or of a truncated p105-NF kappa B1 cDNA that codes for p50-NF kappa B1, restores MHC class I expression in Ad12E1-transformed cells. These data demonstrate that downregulation of MHC class I expression in Ad12E1-transformed cells is due to interference with processing of p105-NF kappa B1 by the Ad12-13S-E1A protein.
我们先前已证明，致癌腺病毒12型（Ad12）早期区域1转化的幼鼠肾细胞中，主要组织相容性复合体（MHC）I类基因的表达受到抑制。MHC I类抗原表达的降低有助于Ad12转化细胞逃避T细胞介导的免疫监视并诱导肿瘤形成。在本研究中，我们表明Ad12E1A对MHC I类表达的抑制是通过MHC I类启动子的H2TF1元件介导的。该元件结合NF-κB和KBF1，这两个因子在体内MHC I类表达的调节中起主要作用。在Ad12E1转化细胞的提取物中，KBF1和NF-κB与H2TF1元件的结合减少。这是由于Ad12-13S-E1A蛋白干扰p105-NF-κB1加工，导致KBF1和NF-κB共有的50 kDa亚基p50-NF-κB1产生减少所致。p105-NF-κB1 cDNA或编码p50-NF-κB1的截短p105-NF-κB1 cDNA的过表达可恢复Ad12E1转化细胞中MHC I类的表达。这些数据表明，Ad12E1转化细胞中MHC I类表达的下调是由于Ad12-13S-E1A蛋白干扰p105-NF-κB1的加工所致。
