Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2 Canada.
Genes Chromosomes Cancer. 2010 Sep;49(9):819-30. doi: 10.1002/gcc.20790.
The underlying cause of human retinoblastoma is complete inactivation of both copies of the RB1 gene. Other chromosome abnormalities, with the most common being extra copies of chromosome arm 6p, are also observed in retinoblastoma. The RB protein has previously been shown to interact with TFAP2 transcription factors. Here, we show that TFAP2A and TFAP2B, which map to chromosome arm 6p, are expressed in the amacrine and horizontal cells of human retina. TFAP2A RNA can readily be detected in retinoblastoma cell lines and tumors; however, the great majority of retinoblastoma cell lines and tumors are completely devoid of TFAP2A protein and TFAP2B RNA/protein. Transfection of TFAP2A and TFAP2B expression constructs into retinoblastoma cells induces apoptosis and inhibits proliferation. Our results suggest that a consequence of loss of RB1 gene function in retinoblastoma cells is inactivation of TFAP2A and TFAP2B function. We propose that inability to differentiate along the amacrine/horizontal cell lineages may underlie retinoblastoma tumor formation.
人类视网膜母细胞瘤的根本原因是 RB1 基因的两个拷贝完全失活。在视网膜母细胞瘤中还观察到其他染色体异常，最常见的是 6p 臂额外的染色体拷贝。RB 蛋白以前曾被证明与 TFAP2 转录因子相互作用。在这里，我们表明，定位在 6p 臂上的 TFAP2A 和 TFAP2B，在人视网膜的无长突细胞和水平细胞中表达。TFAP2A RNA 可在视网膜母细胞瘤细胞系和肿瘤中轻易检测到；然而，绝大多数视网膜母细胞瘤细胞系和肿瘤完全缺乏 TFAP2A 蛋白和 TFAP2B RNA/蛋白。TFAP2A 和 TFAP2B 表达构建体转染入视网膜母细胞瘤细胞中可诱导细胞凋亡并抑制增殖。我们的结果表明，RB1 基因功能丧失在视网膜母细胞瘤细胞中的后果是 TFAP2A 和 TFAP2B 功能失活。我们提出，不能沿着无长突细胞/水平细胞谱系分化可能是视网膜母细胞瘤肿瘤形成的基础。
