Adenovirus serotype 5 E1A sensitizes tumor cells to NKG2D-dependent NK cell lysis and tumor rejection.
Adenovirus serotype 5 E1A sensitizes tumor cells to NKG2D-dependent NK cell lysis and tumor rejection.
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DOI：
10.1084/jem.20050240
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发表时间：
2005-12-05
影响因子：
15.3
通讯作者：
Lanier, Lewis L
中科院分区：
文献类型：
--
作者：
Routes, John M;Ryan, Sharon;Morris, Kristin;Takaki, Rayna;Cerwenka, Adelheid;Lanier, Lewis L
腺病毒血清型5（Ad 5）E1 A癌基因的表达使肿瘤细胞对体内自然杀伤（NK）细胞介导的杀伤和肿瘤排斥敏感。这些作用取决于E1 A结合转录辅衔接蛋白p300的能力。为了检验E1 A上调NKG 2D激活受体识别的配体的假设，我们用Ad 5-E1 A或不与p300相互作用的E1 A突变体（E1 A-Δp300）稳定转染了高度致瘤性的小鼠纤维肉瘤细胞系MCA-205。在4个独立衍生的MCA-205转染子中，Ad 5-E1 A（而非E1 A-Δp300）上调NKG 2D配体视黄酸早期诱导型（RAE）-1（而非鼠ULBP样转录物1（另一种NKG 2D配体））的表达。通过E1 A上调RAE-1靶向MCA-205肿瘤细胞以被NK细胞裂解，导致体内NKG 2D依赖性肿瘤排斥。此外，E1 A对NKG 2D配体的上调并不限于小鼠肿瘤细胞，因为E1 A还增加了原代幼小鼠肾细胞、人MB 435 S乳腺癌细胞和人H4纤维肉瘤细胞上NKG 2D配体的表达。
The expression of the Adenovirus serotype 5 (Ad5) E1A oncogene sensitizes tumor cells to natural killer (NK) cell–mediated killing and tumor rejection in vivo. These effects are dependent on the ability of E1A to bind the transcriptional coadaptor protein p300. To test the hypothesis that E1A up-regulates ligands recognized by the NKG2D-activating receptor, we stably transfected the highly tumorigenic mouse fibrosarcoma cell line MCA-205 with Ad5-E1A or a mutant form of E1A that does not interact with p300 (E1A-Δp300). Ad5-E1A, but not E1A-Δp300, up-regulated the expression of the NKG2D ligand retinoic acid early inducible (RAE)-1, but not murine ULBP-like transcript 1, another NKG2D ligand, in four independently derived MCA-205 transfectants. The up-regulation of RAE-1 by E1A targeted MCA-205 tumor cells to lysis by NK cells, resulting in NKG2D-dependent tumor rejection in vivo. Moreover, the up-regulation of NKG2D ligands by E1A was not limited to mouse tumor cells, as E1A also increased the expression of NKG2D ligands on primary baby mouse kidney cells, human MB435S breast cancer cells, and human H4 fibrosarcoma cells.