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.

Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets / Ferretti, Elisabetta; DI MARCOTULLIO, Lucia; M., Gessi; T., Mattei; Greco, Azzura; Po, Agnese; DE SMAELE, Enrico; Giangaspero, Felice; R., Riccardi; C., Di Rocco; S., Pazzaglia; Maroder, Marella; Alimandi, Maurizio; Screpanti, Isabella; Gulino, Alberto. - In: ONCOGENE. - ISSN 0950-9232. - STAMPA. - 25:55(2006), pp. 7267-7273. [10.1038/sj.onc.1209716]

Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets

FERRETTI, ELISABETTA;DI MARCOTULLIO, LUCIA;GRECO, Azzura;PO, AGNESE;DE SMAELE, Enrico;GIANGASPERO, FELICE;MARODER, Marella;ALIMANDI, MAURIZIO;SCREPANTI, Isabella;GULINO, Alberto
2006

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.
2006
alternative splicing; erbb-4; gli1; hedgehog; medulloblastoma
01 Pubblicazione su rivista::01a Articolo in rivista
Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets / Ferretti, Elisabetta; DI MARCOTULLIO, Lucia; M., Gessi; T., Mattei; Greco, Azzura; Po, Agnese; DE SMAELE, Enrico; Giangaspero, Felice; R., Riccardi; C., Di Rocco; S., Pazzaglia; Maroder, Marella; Alimandi, Maurizio; Screpanti, Isabella; Gulino, Alberto. - In: ONCOGENE. - ISSN 0950-9232. - STAMPA. - 25:55(2006), pp. 7267-7273. [10.1038/sj.onc.1209716]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/362834
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