1. Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets
- Author
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Isabella Screpanti, Alberto Gulino, C. Di Rocco, L Di Marcotullio, Marella Maroder, Felice Giangaspero, Riccardo Riccardi, E De Smaele, Marco Gessi, Simonetta Pazzaglia, Agnese Po, Elisabetta Ferretti, Tiziana Mattei, Maurizio Alimandi, and Azzura Greco
- Subjects
Cytoplasm ,Cancer Research ,medicine.medical_specialty ,Receptor, ErbB-4 ,alternative splicing ,erbb-4 ,gli1 ,hedgehog ,medulloblastoma ,Biology ,environment and public health ,CYT-1 ,ErbB4 ,Mice ,CYT-2 ,ErbB ,GLI1 ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Hedgehog Proteins ,Molecular Biology ,Hedgehog ,PI3K/AKT/mTOR pathway ,DNA Primers ,Base Sequence ,Reverse Transcriptase Polymerase Chain Reaction ,Alternative splicing ,Prognosis ,Hedgehog signaling pathway ,Cell biology ,ErbB Receptors ,Alternative Splicing ,enzymes and coenzymes (carbohydrates) ,Endocrinology ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,embryonic structures ,cardiovascular system ,biology.protein ,Neuregulin ,Signal transduction ,Medulloblastoma ,Signal Transduction - Abstract
Medulloblastoma (MB) results from aberrant development of cerebellar neurons in which altered hedgehog (Hh) signalling plays a major role. We investigated the possible influence of Hh signalling on ErbB-receptor expression in MB, in particular that of the ErbB-4 CYT-1 and CYT-2 isoforms generated by alternative splicing of the cytoplasmic domain. ErbB-4 expression was downregulated in Hh-induced MBs from Patched-1(+/-) mice. Hh signalling (reflected by enhanced expression of the Gli1 transcription factor) inhibited ErbB-4 expression in mouse cerebellar granule progenitors and human MB cells. Analysis of 26 human primary MBs revealed a subset of 11 tumors characterized by low Gli1 levels, upregulated ErbB-4 expression and increased CYT-1:CYT-2 ratios. Interestingly, CYT-1 and Gli1 levels were inversely correlated. ErbB-4 CYT-1 and CYT-2 had different phenotypic effects in cultured MB cells: in response to neuregulin treatment, CYT-2 overexpression inhibited proliferation whereas CYT-1, which includes a phosphatidylinositol 3-kinase (PI3K)-binding site that is missing in CYT-2, enhanced resistance to starvation- and etoposide-induced apoptosis by activating PI3K/Akt signalling. CYT-1:CYT-2 ratios displayed correlation with tumor histotype and ErbB-2 levels, which are established prognostic indices for MB. These findings demonstrate that low-level Hh signalling in human MB is associated with the selective maintenance of high ErbB-4 CYT-1 expression, an alteration that exerts tumor-promoting effects.
- Published
- 2006
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