SPLICING · Splice variants as modifiers of the Patched-Hedgehog signaling pathway
6РП — Действия „Мария Кюри“
- Период
- 2006-03-30 → 2008-03-29
- Финансиране от ЕС
- 167 055 €
- Участници
- 1
- Схема
- IIF
Линиите свързват координатора с партньорите.
Накратко на български
Вариантите на сплайсване при протеините в пътя на Hedgehog, като тези при гените PTCH1 и GLI1, определят как се предават сигналите в клетката. Анализът им помага да се разбере как се регулират процеси, свързани с туморопотибни и туморосупресорни функции.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - SPLICING (Splice variants as modifiers of the Patched-Hedgehog signalling pathway)
During these two years, I investigated the functional significance of splice variants involved in hedgehog (HH) signalling pathway. In the first project step, I performed in-silico screening to identify splice variants in the HH signalling components. Based on the results from several databases, I found 39 putative alternative splicing variants from 14 genes which were HH signalling components. These candidates were placed in a priorities' order based on novelty and putative function. Among these candidates, I focused on the variations of both the tumour suppressor gene, patched 1 (PTCH1), and the oncogene, glioma-associated oncogene 1 (GLI1). During the PTCH1 variants analysis, we identified a novel first exon and demonstrated the unique biological properties of the PTCH1 isoforms which were generated by alternative first exon usage. This finding was published in 'Oncogene' (vol. 27, pages 4889-4896, 2007). In this article, we proposed the dynamic regulation of HH signalling by PTCH1 variants. As part of the GLI1 variants' analysis, we identified a novel human GLI1 variant, which was generated by skipping exons 2 and 3 and encoding an N-terminal truncated GLI1 protein. We examined the functional properties of GLI1 splice variants, including its transcriptional regulation, activity and cellular localisation. This finding was published in 'J. Biol. Chem.' (online on March 31, 2008). In addition, we also identified mouse GLI1 variants and investigated their regulation and roles in HH signalling (manuscript, 2008).
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
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.
Оригинален текст от CORDIS (на английски).
Участници
- KAROLINSKA INSTITUTET · STOCKHOLMКоординаторШвеция
Връзки
Данни: CORDIS, © Европейски съюз