Alternative splicing of theErbB-4 cytoplastic domain and its regulation by hedgehog signaling identif distinct medulloblastoma subsets

Marco Gessi, Riccardo Riccardi, Concezio Di Rocco, E. Ferretti, L. Di Marcotullio, M. Gessi, T. Mattei, A. Greco, A. Po, E. De Smaele, F. Giangaspero, S. Pazzaglia, M. Maroder, M. Alimandi, I. Screpanti, A. Gulino

Risultato della ricerca: Contributo in rivistaArticolo in rivista

38 Citazioni (Scopus)

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
Lingua originaleEnglish
pagine (da-a)7267-7273
Numero di pagine7
RivistaOncogene
Volume25
DOI
Stato di pubblicazionePubblicato - 2006

Keywords

  • CYT-1
  • CYT-2
  • ErbB4
  • medulloblastoma

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