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Splice variants as modifiers of the Patched-Hedgehog signaling pathway


The Patched-Hedgehog signalling pathway is considered to be instrumental for normal developmental patterns but is also implicated in a number of cancer transformation processes that were recently found to include, basal cell carcinomas, but also pancreatic, digestive track and lung cancers. Studies, mainly in Drosophila, have allowed the dissection of the major components of this signal transduction system, that is the Hedgehog receptor Patched, the membrane signalling protein Smoothened, the intracellular transducers Fused, Suppressor of Fused and Costal 2 and the transcription factor Cubitus Interruptus.

However careful analysis of this pathway in mammalian systems revealed a higher complexity than Drosophila, and this is exemplified by the duplication or triplication of some of these components. Humans, for example, have three Hedgehog ligands, two Patched receptors and three Cubitus Interruptus homologs. Moreover the process of alternative pre-mRNA splicing has revealed additional component comple xity. For example GLI1, a Cubitus Interruptus human homolog, was found to express three different mRNAs, each with a unique combination of 5- untranslated exons that confer distinct capacities in translational efficiency.

The focus of this proposal is to expand on recent findings from our laboratory that suggest widespread splicing variation in components of this pathway. Specifically a Patched 1 variant that includes a novel first exon has been identified. Expression of this variant is up regulated by Hedgehog signalling and its functional properties are characterized by a pathway inhibitory capacity (Shimokawa et al, FEBS Lett. 578, 157-162, 2004). Additionally analysis of GLI1 expression revealed further complexity in the 5- exons, which is highly likely t o have functional implications. We would like to continue these studies and address whether targeting specific variants may represent a means to achieve a highly selective disease therapy.

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