HIPK2 sustains apoptotic response by phosphorylating Che-1/AATF and promoting its degradation

Che-1/AATF is an RNA polymerase II-binding protein that is involved in the regulation of gene transcription, which undergoes stabilization and accumulation in response to DNA damage. We have previously demonstrated that following apoptotic induction, Che-1 protein levels are downregulated through it...

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Main Authors:	De Nicola, F, Catena, V, Rinaldo, C, Bruno, T, Iezzi, S, Sorino, C, Desantis, A, Camerini, S, Crescenzi, M, Floridi, A, Passananti, C, Soddu, S, Fanciulli, M
Format:	Online
Language:	English
Published:	Nature Publishing Group 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225224/

id	pubmed-4225224
recordtype	oai_dc
spelling	pubmed-42252242014-11-17 HIPK2 sustains apoptotic response by phosphorylating Che-1/AATF and promoting its degradation De Nicola, F Catena, V Rinaldo, C Bruno, T Iezzi, S Sorino, C Desantis, A Camerini, S Crescenzi, M Floridi, A Passananti, C Soddu, S Fanciulli, M Original Article Che-1/AATF is an RNA polymerase II-binding protein that is involved in the regulation of gene transcription, which undergoes stabilization and accumulation in response to DNA damage. We have previously demonstrated that following apoptotic induction, Che-1 protein levels are downregulated through its interaction with the E3 ligase HDM2, which leads to Che-1 degradation by ubiquitylation. This interaction is mediated by Pin1, which determines a phosphorylation-dependent conformational change. Here we demonstrate that HIPK2, a proapoptotic kinase, is involved in Che-1 degradation. HIPK2 interacts with Che-1 and, upon genotoxic stress, phosphorylates it at specific residues. This event strongly increases HDM2/Che-1 interaction and degradation of Che-1 protein via ubiquitin-dependent proteasomal system. In agreement with these findings, we found that HIPK2 depletion strongly decreases Che-1 ubiquitylation and degradation. Notably, Che-1 overexpression strongly counteracts HIPK2-induced apoptosis. Our results establish Che-1 as a new HIPK2 target and confirm its important role in the cellular response to DNA damage. Nature Publishing Group 2014-09 2014-09-11 /pmc/articles/PMC4225224/ /pubmed/25210797 http://dx.doi.org/10.1038/cddis.2014.381 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	De Nicola, F Catena, V Rinaldo, C Bruno, T Iezzi, S Sorino, C Desantis, A Camerini, S Crescenzi, M Floridi, A Passananti, C Soddu, S Fanciulli, M
spellingShingle	De Nicola, F Catena, V Rinaldo, C Bruno, T Iezzi, S Sorino, C Desantis, A Camerini, S Crescenzi, M Floridi, A Passananti, C Soddu, S Fanciulli, M HIPK2 sustains apoptotic response by phosphorylating Che-1/AATF and promoting its degradation
author_facet	De Nicola, F Catena, V Rinaldo, C Bruno, T Iezzi, S Sorino, C Desantis, A Camerini, S Crescenzi, M Floridi, A Passananti, C Soddu, S Fanciulli, M
author_sort	De Nicola, F
title	HIPK2 sustains apoptotic response by phosphorylating Che-1/AATF and promoting its degradation
title_short	HIPK2 sustains apoptotic response by phosphorylating Che-1/AATF and promoting its degradation
title_full	HIPK2 sustains apoptotic response by phosphorylating Che-1/AATF and promoting its degradation
title_fullStr	HIPK2 sustains apoptotic response by phosphorylating Che-1/AATF and promoting its degradation
title_full_unstemmed	HIPK2 sustains apoptotic response by phosphorylating Che-1/AATF and promoting its degradation
title_sort	hipk2 sustains apoptotic response by phosphorylating che-1/aatf and promoting its degradation
description	Che-1/AATF is an RNA polymerase II-binding protein that is involved in the regulation of gene transcription, which undergoes stabilization and accumulation in response to DNA damage. We have previously demonstrated that following apoptotic induction, Che-1 protein levels are downregulated through its interaction with the E3 ligase HDM2, which leads to Che-1 degradation by ubiquitylation. This interaction is mediated by Pin1, which determines a phosphorylation-dependent conformational change. Here we demonstrate that HIPK2, a proapoptotic kinase, is involved in Che-1 degradation. HIPK2 interacts with Che-1 and, upon genotoxic stress, phosphorylates it at specific residues. This event strongly increases HDM2/Che-1 interaction and degradation of Che-1 protein via ubiquitin-dependent proteasomal system. In agreement with these findings, we found that HIPK2 depletion strongly decreases Che-1 ubiquitylation and degradation. Notably, Che-1 overexpression strongly counteracts HIPK2-induced apoptosis. Our results establish Che-1 as a new HIPK2 target and confirm its important role in the cellular response to DNA damage.
publisher	Nature Publishing Group
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225224/
_version_	1613154081366343680

HIPK2 sustains apoptotic response by phosphorylating Che-1/AATF and promoting its degradation

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