TAp73 isoforms antagonize Notch signalling in SH-SY5Y neuroblastomas and in primary neurones

Claudie Hooper, Mahvash Tavassoli, J. Paul Chapple, Dafe Uwanogho, Richard Goodyear, Gerry Melino, Simon Lovestone, Richard Killick

Research output: Contribution to journalArticle

Abstract

p73, like Notch, has been implicated in neurodevelopment and in the maintenance of the mature central nervous system. In this study, by the use of reporter-gene assays, we demonstrate that C-promoter binding factor-1 (CBF-1)-dependent gene transcription driven by the Notch-1 intracellular domain (N1ICD) is potently antagonized by exogenously expressed transactivating (TA) p73 splice variants in SH-SY5Y neuroblastomas and in primary neurones. Time course analysis indicated that the inhibitory effects of TAp73 are direct and are not mediated via the product of a downstream target gene. We found that endogenous TAp73 stabilized by either c-Abl or cisplatin treatment also potently antagonized N1ICD/CBF-1-dependent gene transcription. Furthermore, western blotting revealed that exogenous TAp73 suppressed endogenous hairy and enhancer of split-1 (HES-1) protein levels and antagonized the increase in HES-1 protein induced by exogenous N1ICD expression. Evidence of a direct physical interaction between N1ICD and TAp73α was demonstrated by co-immunoprecipitation. Using Notch deletion constructs, we demonstrate that TAp73α binds the N1ICD in a region C-terminal of aa 2094. Interestingly, ΔNp73α and TAp73αR292H also co-purified with N1ICD, but neither inhibited N1ICD/CBF-1-dependent transcription. This suggests that an intact transactivation (TA) domain and the ability to bind DNA are necessary for TAp73 to antagonize Notch signalling. Finally we found that TAp73α reversed the N1ICD-mediated repression of retinoic acid-induced differentiation of SH-SY5Y neuroblastomas, providing functional evidence for an inhibitory effect of TAp73α on notch signalling. Collectively, these findings may have ramifications for neurodevelopment, neurodegeneration and oncogenesis.

Original languageEnglish
Pages (from-to)989-999
Number of pages11
JournalJournal of Neurochemistry
Volume99
Issue number3
DOIs
Publication statusPublished - Nov 2006

Keywords

  • Development
  • Neurodegeneration
  • Notch
  • Oncogenesis
  • p53
  • p73

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Hooper, C., Tavassoli, M., Chapple, J. P., Uwanogho, D., Goodyear, R., Melino, G., Lovestone, S., & Killick, R. (2006). TAp73 isoforms antagonize Notch signalling in SH-SY5Y neuroblastomas and in primary neurones. Journal of Neurochemistry, 99(3), 989-999. https://doi.org/10.1111/j.1471-4159.2006.04142.x