Activation of the BCL2 Promoter in Response to Hedgehog/GLI Signal Transduction Is Predominantly Mediated by GLI2

胶质2 胶质1 转录因子 生物 刺猬 刺猬信号通路 癌症研究 癌变 信号转导 细胞生物学 发起人 分子生物学 基因表达 基因 遗传学
作者
Gerhard Regl,Maria Kasper,Harald Schnidar,Thomas Eichberger,Graham W. Neill,Michael P. Philpott,Harald Esterbauer,Cornelia Hauser‐Kronberger,Anna‐Maria Frischauf,Fritz Aberger
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:64 (21): 7724-7731 被引量:228
标识
DOI:10.1158/0008-5472.can-04-1085
摘要

Abstract Aberrant activation of the Hedgehog (HH)/GLI signaling pathway has been implicated in the development of basal cell carcinoma (BCC). The zinc finger 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-specific activation of the human BCL2 promoter and that the selective induction of BCL2 expression depends on the zinc finger 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.

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