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Insulin Receptor Isoforms Differently Regulate Cell Proliferation and Apoptosis in the Ligand-Occupied and Unoccupied State

The insulin receptor (IR) presents two isoforms (IR-A and IR-B) that differ for the α-subunit C-terminal. Both isoforms are expressed in all human cells albeit in different proportions, yet their functional properties-when bound or unbound to insulin-are not well characterized. From a cell model dep...

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Autores principales: Massimino, Michele, Sciacca, Laura, Parrinello, Nunziatina Laura, Scalisi, Nunzio Massimo, Belfiore, Antonino, Vigneri, Riccardo, Vigneri, Paolo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395753/
https://www.ncbi.nlm.nih.gov/pubmed/34445431
http://dx.doi.org/10.3390/ijms22168729
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author Massimino, Michele
Sciacca, Laura
Parrinello, Nunziatina Laura
Scalisi, Nunzio Massimo
Belfiore, Antonino
Vigneri, Riccardo
Vigneri, Paolo
author_facet Massimino, Michele
Sciacca, Laura
Parrinello, Nunziatina Laura
Scalisi, Nunzio Massimo
Belfiore, Antonino
Vigneri, Riccardo
Vigneri, Paolo
author_sort Massimino, Michele
collection PubMed
description The insulin receptor (IR) presents two isoforms (IR-A and IR-B) that differ for the α-subunit C-terminal. Both isoforms are expressed in all human cells albeit in different proportions, yet their functional properties-when bound or unbound to insulin-are not well characterized. From a cell model deprived of the Insulin-like Growth Factor 1 Receptor (IGF1-R) we therefore generated cells exhibiting no IR (R-shIR cells), or only human IR-A (R-shIR-A), or exclusively human IR-B (R-shIR-B) and we studied the specific effect of the two isoforms on cell proliferation and cell apoptosis. In the absence of insulin both IR-A and IR-B similarly inhibited proliferation but IR-B was 2–3 fold more effective than IR-A in reducing resistance to etoposide-induced DNA damage. In the presence of insulin, IR-A and IR-B promoted proliferation with the former significantly more effective than the latter at increasing insulin concentrations. Moreover, only insulin-bound IR-A, but not IR-B, protected cells from etoposide-induced cytotoxicity. In conclusion, IR isoforms have different effects on cell proliferation and survival. When unoccupied, IR-A, which is predominantly expressed in undifferentiated and neoplastic cells, is less effective than IR-B in protecting cells from DNA damage. In the presence of insulin, particularly when present at high levels, IR-A provides a selective growth advantage.
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spelling pubmed-83957532021-08-28 Insulin Receptor Isoforms Differently Regulate Cell Proliferation and Apoptosis in the Ligand-Occupied and Unoccupied State Massimino, Michele Sciacca, Laura Parrinello, Nunziatina Laura Scalisi, Nunzio Massimo Belfiore, Antonino Vigneri, Riccardo Vigneri, Paolo Int J Mol Sci Brief Report The insulin receptor (IR) presents two isoforms (IR-A and IR-B) that differ for the α-subunit C-terminal. Both isoforms are expressed in all human cells albeit in different proportions, yet their functional properties-when bound or unbound to insulin-are not well characterized. From a cell model deprived of the Insulin-like Growth Factor 1 Receptor (IGF1-R) we therefore generated cells exhibiting no IR (R-shIR cells), or only human IR-A (R-shIR-A), or exclusively human IR-B (R-shIR-B) and we studied the specific effect of the two isoforms on cell proliferation and cell apoptosis. In the absence of insulin both IR-A and IR-B similarly inhibited proliferation but IR-B was 2–3 fold more effective than IR-A in reducing resistance to etoposide-induced DNA damage. In the presence of insulin, IR-A and IR-B promoted proliferation with the former significantly more effective than the latter at increasing insulin concentrations. Moreover, only insulin-bound IR-A, but not IR-B, protected cells from etoposide-induced cytotoxicity. In conclusion, IR isoforms have different effects on cell proliferation and survival. When unoccupied, IR-A, which is predominantly expressed in undifferentiated and neoplastic cells, is less effective than IR-B in protecting cells from DNA damage. In the presence of insulin, particularly when present at high levels, IR-A provides a selective growth advantage. MDPI 2021-08-13 /pmc/articles/PMC8395753/ /pubmed/34445431 http://dx.doi.org/10.3390/ijms22168729 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Brief Report
Massimino, Michele
Sciacca, Laura
Parrinello, Nunziatina Laura
Scalisi, Nunzio Massimo
Belfiore, Antonino
Vigneri, Riccardo
Vigneri, Paolo
Insulin Receptor Isoforms Differently Regulate Cell Proliferation and Apoptosis in the Ligand-Occupied and Unoccupied State
title Insulin Receptor Isoforms Differently Regulate Cell Proliferation and Apoptosis in the Ligand-Occupied and Unoccupied State
title_full Insulin Receptor Isoforms Differently Regulate Cell Proliferation and Apoptosis in the Ligand-Occupied and Unoccupied State
title_fullStr Insulin Receptor Isoforms Differently Regulate Cell Proliferation and Apoptosis in the Ligand-Occupied and Unoccupied State
title_full_unstemmed Insulin Receptor Isoforms Differently Regulate Cell Proliferation and Apoptosis in the Ligand-Occupied and Unoccupied State
title_short Insulin Receptor Isoforms Differently Regulate Cell Proliferation and Apoptosis in the Ligand-Occupied and Unoccupied State
title_sort insulin receptor isoforms differently regulate cell proliferation and apoptosis in the ligand-occupied and unoccupied state
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395753/
https://www.ncbi.nlm.nih.gov/pubmed/34445431
http://dx.doi.org/10.3390/ijms22168729
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