Medulloblastoma (MB) results from aberrant development of cerebellar neurons in which alteredhed gehog (Hh) signalling plays a major role. We investigatedthe possible influence of Hh signalling on ErbB-receptor expression in MB, in particular that of the ErbB-4 CYT-1 andCYT-2 isoforms generatedby alternative splicing of the cytoplasmic domain. ErbB-4 expression was downregulated in Hh-induced MBs from Patched-1þ/ mice. Hh signalling (reflectedby enhancedexpress ion of the Gli1 transcription factor) inhibitedErbB-4 expression in mouse cerebellar granule progenitors andhuman MB cells. Analysis of 26 human primary MBs revealeda subset of 11 tumors characterizedby low Gli1 levels, upregulatedErbB-4 expression andincreasedCYT-1: CYT-2 ratios. Interestingly, CYT-1 andGli1 levels were inversely correlated. ErbB-4 CYT-1 andC YT-2 hadd ifferent phenotypic effects in culturedMB cells: in response to neuregulin treatment, CYT-2 overexpression inhibitedpr oliferation whereas CYT-1, which includes a phosphatidylinositol 3-kinase (PI3K)-binding site that is missing in CYT-2, enhanced resistance to starvation- andet oposide-induced apoptosis by activating PI3K/Akt signalling. CYT-1:CYT-2 ratios displayed correlation with tumor histotype and ErbB-2 levels, which are establishedpr ognostic indices for MB. These findings demonstrate that low-level Hh signalling in human MB is associatedw ith the selective maintenance of high ErbB-4 CYT-1 expression, an alteration that exerts tumor-promoting effects.
Alternative splicing of ErbB-4 cdytoplasmic domain and regulation by hedgehog signaling identità distinct medulloblastoma subsets / Ferretti, E., Di Marcotullio, L., Gessi, M., Mattei, T., Greco, A., Po, A., De Smaele, E., Giangaspero, F., Riccardi, R., Di Rocco, C., Pazzaglia, S., Maroder, M., M, A., Screpanti, I., And Gulino, A.R., Italy,. - In: ONCOGENE. - ISSN 0950-9232. - (2006).
Alternative splicing of ErbB-4 cdytoplasmic domain and regulation by hedgehog signaling identità distinct medulloblastoma subsets
FERRETTI EPrimo
;PO A;GIANGASPERO F;SCREPANTI I;
2006
Abstract
Medulloblastoma (MB) results from aberrant development of cerebellar neurons in which alteredhed gehog (Hh) signalling plays a major role. We investigatedthe possible influence of Hh signalling on ErbB-receptor expression in MB, in particular that of the ErbB-4 CYT-1 andCYT-2 isoforms generatedby alternative splicing of the cytoplasmic domain. ErbB-4 expression was downregulated in Hh-induced MBs from Patched-1þ/ mice. Hh signalling (reflectedby enhancedexpress ion of the Gli1 transcription factor) inhibitedErbB-4 expression in mouse cerebellar granule progenitors andhuman MB cells. Analysis of 26 human primary MBs revealeda subset of 11 tumors characterizedby low Gli1 levels, upregulatedErbB-4 expression andincreasedCYT-1: CYT-2 ratios. Interestingly, CYT-1 andGli1 levels were inversely correlated. ErbB-4 CYT-1 andC YT-2 hadd ifferent phenotypic effects in culturedMB cells: in response to neuregulin treatment, CYT-2 overexpression inhibitedpr oliferation whereas CYT-1, which includes a phosphatidylinositol 3-kinase (PI3K)-binding site that is missing in CYT-2, enhanced resistance to starvation- andet oposide-induced apoptosis by activating PI3K/Akt signalling. CYT-1:CYT-2 ratios displayed correlation with tumor histotype and ErbB-2 levels, which are establishedpr ognostic indices for MB. These findings demonstrate that low-level Hh signalling in human MB is associatedw ith the selective maintenance of high ErbB-4 CYT-1 expression, an alteration that exerts tumor-promoting effects.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
