Activation of the BCL2 promoter in response to hedgehog/GLI signal transduction is predominantly mediated by GLI2
Activation of the BCL2 promoter in response to hedgehog/GLI signal transduction is predominantly mediated by GLI2
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DOI：
10.1158/0008-5472.can-04-1085
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发表时间：
2004-11-01
期刊：
影响因子：
11.2
通讯作者：
Aberger, F
中科院分区：
文献类型：
--
作者：
Regl, G;Kasper, M;Aberger, F
Hedgehog (HH)/GLI 信号通路的异常激活与基底细胞癌 (BCC) 的发生有关。锌林格转录因子 GLI1 和 GLI2 被认为是表皮细胞中 HH 信号的介质，尽管它们的致瘤性质及其对肿瘤发生的相对贡献知之甚少。为了阐明这些转录因子在表皮瘤形成中各自的作用，我们筛选了人表皮细胞中优先受 GLI1 或 GLI2 调节的基因。我们在此表明，与 GLI1 相比，关键抗凋亡因子 BCL2 的表达主要由 GLI2 激活。详细的启动子分析和凝胶位移测定确定了人 BCL2 顺式调控区中的三个 GLI 结合位点。我们发现这些结合位点之一对于赋予人 BCL2 启动子 GLI2 特异性激活至关重要，并且 BCL2 表达的选择性诱导取决于 GLI2 的锌林格 DNA 结合域。在体内，GLI2和BCL2在毛囊和BCC的外根鞘以及浸润BCC肿瘤岛的浆细胞中共表达。基于后者的观察，我们分析了浆细胞源性肿瘤，发现浆细胞瘤患者的肿瘤细胞中 GLI2 和 BCL2 强表达，这表明 HH/GLI 信号传导参与浆细胞源性恶性肿瘤的发生。结果揭示了 GLI2 在激活促生存因子 BCL2 中的核心作用，这可能代表了与不适当的 HH 信号传导相关的癌症发生或维持的重要机制。
Aberrant activation of the Hedgehog (HH)/GLI signaling pathway has been implicated in the development of basal cell carcinoma (BCC). The zinc ringer transcription factors GLI1 and GLI2 are considered mediators of the HH signal in epidermal cells, although their tumorigenic nature and their relative contribution to tumorigenesis are only poorly understood. To shed light on the respective role of these transcription factors in epidermal neoplasia, we screened for genes preferentially regulated either by GLI1 or GLI2 in human epidermal cells. We show here that expression of the key antiapoptotic factor BCL2 is predominantly activated by GLI2 compared with GLI1 Detailed promoter analysis and gel shift assays identified three GLI binding sites in the human BCL2 cis-regulatory region. We found that one of these binding sites is critical for conferring GLI2-speciric activation of the human BCL2 promoter and that the selective induction of BCL2 expression depends on the zinc ringer DNA binding domain of GLI2. In vivo, GLI2 and BCL2 were coexpressed in the outer root sheath of hair follicles and BCC and in plasma cells that infiltrated BCC tumor islands. On the basis of the latter observation, we analyzed plasma cell-derived tumors and found strong expression of GLI2 and BCL2 in neoplastic cells of plasmacytoma patients, implicating HH/GLI signaling in the development of plasma cell-derived malignancies. The results reveal a central role for GLI2 in activating the prosurvival factor BCL2, which may represent an important mechanism in the development or maintenance of cancers associated with inappropriate HH signaling.