Post-transcriptional Regulation of the GLI1 Oncogene by the Expression of Alternative 5′ Untranslated Regions

Abstract

The oncogene GLI1 is involved in the formation of basal cell carcinoma and other tumor types as a result of the aberrant signaling of the Sonic hedgehog-Patched pathway. In this study, we have identified alternative GLI1 transcripts that differ in their 5 untranslated regions (UTRs) and are generated by exon skipping. These are denoted ␣-UTR, ␤-UTR, and ␥-UTR according to the number of noncoding exons possessed (three, two, and one, respectively). The ␣-and ␤-UTR forms represent the major Gli1 transcripts expressed in mouse tissues, whereas the ␥-UTR is present at relatively low levels but is markedly induced in mouse skin treated with 12-Otetradecanoylphorbol 13-acetate. Transcripts corresponding to the murine ␤ and ␥ forms were identified in human tissues, but significantly, only the ␥-UTR form was present in basal cell carcinomas and in proliferating cultures of a keratinocyte cell line. Flow cytometry analysis determined that the ␥-UTR variant expresses a heterologous reporter gene 14 -23-fold higher than the ␣-UTR and 5-13-fold higher than the ␤-UTR in a variety of cell types. Because expression of the ␥-UTR variant correlates with proliferation, consistent with a role for GLI1 in growth promotion, up-regulation of GLI1 expression through skipping of 5 noncoding exons may be an important tumorigenic mechanism.

Gli Transcription Factors Mediate the Oncogenic Transformation of Prostate Basal Cells Induced by a Kras-Androgen Receptor Axis

“…Both Gli1 and 2 proteins contain the activator domain; however, Gli2, but not Gli1, has the inhibitory domain in the N terminus. This is in line with evidence showing that aberrant expression of Gli1 is involved in the formation of basal cell carcinoma (42,43). In contrast, expression of Gli2 is regulated by p63, and p63-Gli2 cross-talk facilitates osteosarcoma progression (44).…”

Distinct roles of first exon variants of the tumor-suppressor Patched1 in Hedgehog signaling

“…Finally, alternative splicing of HH signaling components has also been reported for PTCH2 (Zaphiropoulos et al, 1999;Rahnama et al, 2004), GLI1 (Wang and Rothnagel, 2001) and GLI2 (Speek et al, 2006). These variants had different protein stabilities and/or biochemical properties.…”

Novel Human Glioma-associated Oncogene 1 (GLI1) Splice Variants Reveal Distinct Mechanisms in the Terminal Transduction of the Hedgehog Signal

“…Moreover, it also acts as a key molecule in the regulation of glioma growth and the self-renewal of cancer stem cells (23,24). Additionally, Wang and Rothnagel (25) have identified splice variants in the 5Ј noncoding region of GLI1. In this report we provide evidence for splicing variations that alter the coding sequence of GLI1.…”