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

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.

Cooperation between GLI and JUN enhances transcription of JUN and selected GLI target genes

“…This is not due to a generally higher activation potential as PTCH activation is comparable. Differences in target gene activation between GLI1 and GLI2act have previously been shown for other promoters (Regl et al, 2004b;Zhao et al, 2006;Eichberger et al, 2008). GLI2act that shows enhanced transcriptional activation compared to fulllength GLI2 (Roessler et al, 2005) has been used as an 'activated GLI2' in vivo and in vitro.…”

Basal cell carcinoma: biology, morphology and clinical implications

“…67 Upregulation of Gli proteins (Figures 18 and 19) has been shown by quantitative reverse transcriptase polymerase chain reaction assay in BCC 68,69 and may play an important role in the initiation of BCC through the activation of the BCL2 gene ( Figure 20). 70 Gli proteins are also downstream regulators of the SHH signaling pathway, leading to increased tRNA expression through the basonuclin gene system 71 and possibly as well through the forkhead/wingedhelix domain transcription factor FOXE-1. 72 Increased FOXM-1 levels, upregulated through shh signalling via Gli1, may be specific for sporadic BCC.…”

“…[79][80][81][82][83] That the two proposed mechanisms of tumorigenesis are complementary is suggested by the fact that shh-expressing cells also manifest increased expression of bcl-2, 84 likely through activation of the Gli proteins that are expressed in the outer root sheath of the normal hair follicle and in BCCs; 65 Gli-2 in particular appears to play an important role in the activation of the BCL2 gene. 70 …”

A Role for Transcription Factor STAT3 Signaling in Oncogene Smoothened-driven Carcinogenesis

“…Although several downstream mediators for BCC development have been described, including BCL2 (20,21), PDGFR␣ (22), CD95 (12,23), and BMI1 (24), we do not know the actual contribution of these mediators to Hh-induced BCC carcinogenesis. Increasing evidence indicate the importance of signaling cross-talks between Hh signaling and other pathways during carcinogenesis, such as PI3K-AKT, p53, wnt, and epidermal growth factor receptor signaling (reviewed in Refs.…”