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Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16(INK4A)

The tumor suppressor p16(INK4A) induces cell cycle arrest and senescence in response to oncogenic transformation and is therefore frequently lost in cancer. p16(INK4A) is also known to accumulate under conditions of oxidative stress. Thus, we hypothesized it could potentially be regulated by reversi...

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Autores principales: Göbl, Christoph, Morris, Vanessa K., van Dam, Loes, Visscher, Marieke, Polderman, Paulien E., Hartlmüller, Christoph, de Ruiter, Hesther, Hora, Manuel, Liesinger, Laura, Birner-Gruenberger, Ruth, Vos, Harmjan R., Reif, Bernd, Madl, Tobias, Dansen, Tobias B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812003/
https://www.ncbi.nlm.nih.gov/pubmed/31539802
http://dx.doi.org/10.1016/j.redox.2019.101316
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author Göbl, Christoph
Morris, Vanessa K.
van Dam, Loes
Visscher, Marieke
Polderman, Paulien E.
Hartlmüller, Christoph
de Ruiter, Hesther
Hora, Manuel
Liesinger, Laura
Birner-Gruenberger, Ruth
Vos, Harmjan R.
Reif, Bernd
Madl, Tobias
Dansen, Tobias B.
author_facet Göbl, Christoph
Morris, Vanessa K.
van Dam, Loes
Visscher, Marieke
Polderman, Paulien E.
Hartlmüller, Christoph
de Ruiter, Hesther
Hora, Manuel
Liesinger, Laura
Birner-Gruenberger, Ruth
Vos, Harmjan R.
Reif, Bernd
Madl, Tobias
Dansen, Tobias B.
author_sort Göbl, Christoph
collection PubMed
description The tumor suppressor p16(INK4A) induces cell cycle arrest and senescence in response to oncogenic transformation and is therefore frequently lost in cancer. p16(INK4A) is also known to accumulate under conditions of oxidative stress. Thus, we hypothesized it could potentially be regulated by reversible oxidation of cysteines (redox signaling). Here we report that oxidation of the single cysteine in p16(INK4A) in human cells occurs under relatively mild oxidizing conditions and leads to disulfide-dependent dimerization. p16(INK4A) is an all α-helical protein, but we find that upon cysteine-dependent dimerization, p16(INK4A) undergoes a dramatic structural rearrangement and forms aggregates that have the typical features of amyloid fibrils, including binding of diagnostic dyes, presence of cross-β sheet structure, and typical dimensions found in electron microscopy. p16(INK4A) amyloid formation abolishes its function as a Cyclin Dependent Kinase 4/6 inhibitor. Collectively, these observations mechanistically link the cellular redox state to the inactivation of p16(INK4A) through the formation of amyloid fibrils.
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spelling pubmed-68120032019-10-30 Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16(INK4A) Göbl, Christoph Morris, Vanessa K. van Dam, Loes Visscher, Marieke Polderman, Paulien E. Hartlmüller, Christoph de Ruiter, Hesther Hora, Manuel Liesinger, Laura Birner-Gruenberger, Ruth Vos, Harmjan R. Reif, Bernd Madl, Tobias Dansen, Tobias B. Redox Biol Research Paper The tumor suppressor p16(INK4A) induces cell cycle arrest and senescence in response to oncogenic transformation and is therefore frequently lost in cancer. p16(INK4A) is also known to accumulate under conditions of oxidative stress. Thus, we hypothesized it could potentially be regulated by reversible oxidation of cysteines (redox signaling). Here we report that oxidation of the single cysteine in p16(INK4A) in human cells occurs under relatively mild oxidizing conditions and leads to disulfide-dependent dimerization. p16(INK4A) is an all α-helical protein, but we find that upon cysteine-dependent dimerization, p16(INK4A) undergoes a dramatic structural rearrangement and forms aggregates that have the typical features of amyloid fibrils, including binding of diagnostic dyes, presence of cross-β sheet structure, and typical dimensions found in electron microscopy. p16(INK4A) amyloid formation abolishes its function as a Cyclin Dependent Kinase 4/6 inhibitor. Collectively, these observations mechanistically link the cellular redox state to the inactivation of p16(INK4A) through the formation of amyloid fibrils. Elsevier 2019-09-03 /pmc/articles/PMC6812003/ /pubmed/31539802 http://dx.doi.org/10.1016/j.redox.2019.101316 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Göbl, Christoph
Morris, Vanessa K.
van Dam, Loes
Visscher, Marieke
Polderman, Paulien E.
Hartlmüller, Christoph
de Ruiter, Hesther
Hora, Manuel
Liesinger, Laura
Birner-Gruenberger, Ruth
Vos, Harmjan R.
Reif, Bernd
Madl, Tobias
Dansen, Tobias B.
Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16(INK4A)
title Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16(INK4A)
title_full Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16(INK4A)
title_fullStr Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16(INK4A)
title_full_unstemmed Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16(INK4A)
title_short Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16(INK4A)
title_sort cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16(ink4a)
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812003/
https://www.ncbi.nlm.nih.gov/pubmed/31539802
http://dx.doi.org/10.1016/j.redox.2019.101316
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