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ΔNp73 antisense activates PUMA and induces apoptosis in neuroblastoma cells


Simões-Wüst, A P; Sigrist, B; Belyanskaya, L; Hopkins Donaldson, S; Stahel, R A; Zangemeister-Wittke, U (2005). ΔNp73 antisense activates PUMA and induces apoptosis in neuroblastoma cells. Journal of Neuro-Oncology, 72(1):29-34.

Abstract

The p73 gene codes for various different protein isoforms. They include proteins expressed under the control of the P1 promoter that contain a transactivation domain and are similar in function to p53 (TAp73 isoforms), as well as proteins regulated by the P2 promoter that lack this domain and function as dominant negative inhibitors of TAp73 and p53 (ΔNp73 isoforms). Whereas TAp73 functions as a tumor suppressor with pro-apoptotic function, ΔNp73 is likely to prevent the induction of apoptosis in tumor cells and to participate in oncogenesis. Here we used a loss-of-function strategy to assess the role of ΔNp73 in SH-SY5Y neuroblastoma cells. An antisense oligonucleotide designed to target ΔNp73 mRNA, but not TAp73, was used to effectively downregulate this transcript. ΔNp73 downregulation was accompanied by increased levels of the pro-apoptotic BH3 family member PUMA at the mRNA and protein level, and by conformational activation of BAX which translocated to mitochondria. These ΔNp73 antisense-mediated alterations led to the induction of apoptosis as detected by decreased cell viability, augmented DNA fragmentation and increased caspase-3 activity in cell lysates. Our results demonstrate the cytoprotective role of ΔNp73 in neuroblastoma and suggest its use as a target for molecular intervention therapy

Abstract

The p73 gene codes for various different protein isoforms. They include proteins expressed under the control of the P1 promoter that contain a transactivation domain and are similar in function to p53 (TAp73 isoforms), as well as proteins regulated by the P2 promoter that lack this domain and function as dominant negative inhibitors of TAp73 and p53 (ΔNp73 isoforms). Whereas TAp73 functions as a tumor suppressor with pro-apoptotic function, ΔNp73 is likely to prevent the induction of apoptosis in tumor cells and to participate in oncogenesis. Here we used a loss-of-function strategy to assess the role of ΔNp73 in SH-SY5Y neuroblastoma cells. An antisense oligonucleotide designed to target ΔNp73 mRNA, but not TAp73, was used to effectively downregulate this transcript. ΔNp73 downregulation was accompanied by increased levels of the pro-apoptotic BH3 family member PUMA at the mRNA and protein level, and by conformational activation of BAX which translocated to mitochondria. These ΔNp73 antisense-mediated alterations led to the induction of apoptosis as detected by decreased cell viability, augmented DNA fragmentation and increased caspase-3 activity in cell lysates. Our results demonstrate the cytoprotective role of ΔNp73 in neuroblastoma and suggest its use as a target for molecular intervention therapy

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:National licences > 142-005
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:1 March 2005
Deposited On:24 Oct 2018 13:38
Last Modified:04 Nov 2018 05:58
Publisher:Springer
ISSN:0167-594X
OA Status:Green
Publisher DOI:https://doi.org/10.1007/s11060-004-3118-8
Related URLs:https://www.swissbib.ch/Search/Results?lookfor=nationallicencespringer101007s1106000431188 (Library Catalogue)

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