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

被引:39
作者
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.
Alimandi, M.
Screpanti, I.
Gulino, A.
机构
[1] Univ Roma La Sapienza, Dept Expt Med & Pathol, I-00161 Rome, Italy
[2] Natl Neurol Inst C Besta, Div Neuropathol, Milan, Italy
[3] Neuromed Inst, Isernia, Italy
[4] Catholic Univ Rome, Dept Pediat, Rome, Italy
[5] Catholic Univ Rome, Inst Neurosurg, Rome, Italy
[6] ENEA CR, Biotechnol Unit, Rome, Italy
[7] Cenci Bolognetti Fdn, Inst Pasteur, Rome, Italy
关键词
medulloblastoma; ErbB-4; alternative splicing; hedgehog; Gli1;
D O I
10.1038/sj.onc.1209716
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:7267 / 7273
页数:7
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