Alternative splicing is observed in ~40-60% of human genes; however, its full impact on human cancers is still not well understood. In this proposal, we will functionally characterize a novel, alternatively spliced transcription factor discovered in the PI's laboratory, namely, tGLI1 (truncated glioma-associated oncogene homolog 1). Belonging to the GLI1 family of zinc finger transcription factors, tGLI1 has an in-frame deletion of entire exon 3 and part of exon 4 of the GLI1 gene. Like GLI1, tGLI1 responds to sonic hedgehog ligand, undergoes nuclear transport, and regulates known GLI1 target genes. However, our preliminary results showed that tGLI1 may differ from GLI1 in regulating tumor phenotypes, transcriptional targets and expression pattern. Glioblastoma multiforme (GBM) xenografts engineered to express tGLI1 appeared to be more aggressive in growth, invasiveness, and angiogenesis than those with GLI1. tGLI1 has gained the ability to enhance expression of several invasion- and angiogenesis-promoting genes. tGLI1 was highly expressed in nearly 50% of GBM specimens we had examined, but undetectable in normal brain or other normal tissues. These observations have led us to hypothesize that the novel tGLI1 transcription factor behaves as a gain-of-function GLI1 that regulates expression of a unique set of genes not targeted by GLI1, and that because of its overexpression in GBM and its ability to enhance genes important for tumor growth, invasion and angiogenesis, tGLI1 supports some of the predominant features of GBM, i.e. high degrees of proliferation, infiltration and vascularity.
Three Specific Aims are proposed to test this hypothesis. (1) Determine whether tGLI1 mediates malignant phenotypes of GBM. There has been no systematic study that investigated the role of tGLI1 in distinctive GBM malignant phenotypes. Here, we will create intracranial GBM xenografts with differential levels of tGLI1 via knock-in and knock-down approaches, examine the xenografts for growth, invasiveness and angiogenesis, and monitor the xenograft-carrying mice for survival. (2) Elucidate the mechanisms by which tGLI1 regulates gene expression in GBM. tGLI1 has gained the ability to enhance expression of several genes; however, the underlying mechanisms for this unique ability is currently unknown. Here, we will investigate two potential mechanisms: a) tGLI1 binds to unique DNA elements, not recognized by GLI1, within its target gene promoters and thereby regulates genes not targeted by GLI1; and b) tGLI1 has gained the ability to interact with transcription regulators that do not interact with GLI1, thereb regulating genes not targeted by GLI1. (3) Investigate alternative splicing process that leads to tGLI1 mRNA synthesis in GBM. Alternative splicing process for tGLI1 mRNA synthesis is presently unknown. We will identify the cis-acting elements within the pre-mRNA and the RNA-binding splicing factors that together mediate alternative splicing for tGLI1 mRNA synthesis. Our study will be the first step towards defining tGLI1 as a novel mediator of GBM malignancy, and understanding the full spectrum of tGLI1 functionality and the molecular basis for tGLI1 mRNA synthesis.
The application has high relevance to human health because the proposed studies address the malignant biology of glioblastoma multiforme (GBM), the most common and deadliest brain cancer in adults. The study goal is to fill a major gap in our understanding of the tGLI1 signaling and its impact on GBM aggressiveness. We anticipate that the results obtained from this proposal will have significant impact on the molecular pathways that drive the malignant phenotypes in GBM.
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