Liu X, Ge R, Westmoreland S, Cooney A J, Tsai S Y, Tsai M J, Ricciardi R P
Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia 19104.
Oncogene. 1994 Aug;9(8):2183-90.
The transcriptional down-regulation of the major histocompatibility complex (MHC) class I antigens in adenovirus type 12 (Ad12) transformed cells gives them the potential to escape immunosurveillance and to form tumors. The enhancer of the class I promoter is the target of transcriptional repression which is mediated by the E1A gene of Ad12. The R2 region within the class I enhancer acts as a negative element in Ad12-transformed cells and exhibits a stronger binding activity than is observed in nontumorigenic Ad5-transformed cells, which are not reduced in class I expression. The R2 element contains a nuclear hormone receptor half-site consensus sequence, AGGTCA, which is required for both the binding activity and the ability of R2 to act as a negative element in Ad12-transformed cells. In this study, we show that an orphan hormone receptor protein, COUP-TF, contributes to the differential R2 binding activity observed between Ad12- and Ad5-transformed cells. Additionally, COUP-TF was shown to bind as a dimer to the R2 element and to use the consensus AGGTCA as one half-site and its 3' flanking sequence as a probable second degenerate half-site. Since COUP-TF can act as a transcriptional repressor, we suggest that the higher COUP-TF binding activity to the R2 element in Ad12-transformed cells contributes to down-regulation of class I transcription and, consequently, tumorigenesis.
12型腺病毒（Ad12）转化细胞中主要组织相容性复合体（MHC）I类抗原的转录下调使它们有逃避免疫监视并形成肿瘤的可能。I类启动子的增强子是转录抑制的靶点，这种抑制由Ad12的E1A基因介导。I类增强子内的R2区域在Ad12转化细胞中作为负性元件起作用，并且与在I类表达未降低的非致瘤性Ad5转化细胞中观察到的相比，表现出更强的结合活性。R2元件包含一个核激素受体半位点共有序列AGGTCA，这对于R2在Ad12转化细胞中的结合活性和作为负性元件的能力都是必需的。在本研究中，我们表明一种孤儿激素受体蛋白COUP-TF促成了在Ad12和Ad5转化细胞之间观察到的R2结合活性差异。此外，COUP-TF被证明以二聚体形式与R2元件结合，并将共有序列AGGTCA用作一个半位点，将其3'侧翼序列用作可能的第二个简并半位点。由于COUP-TF可以作为转录抑制因子，我们认为在Ad12转化细胞中COUP-TF对R2元件的更高结合活性有助于I类转录的下调，从而导致肿瘤发生。
