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Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells
Type 2 diabetes (T2D) is characterized by insulin resistance and reduced functional β-cell mass. Developmental differences, failure of adaptive expansion and loss of β-cells via β-cell death or de-differentiation have emerged as the possible causes of this reduced β-cell mass. We hypothesized that t...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933882/ https://www.ncbi.nlm.nih.gov/pubmed/27380896 http://dx.doi.org/10.1038/srep28461 |
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author | Tiwari, Shiwani Roel, Chris Tanwir, Mansoor Wills, Rachel Perianayagam, Nidhi Wang, Peng Fiaschi-Taesch, Nathalie M. |
author_facet | Tiwari, Shiwani Roel, Chris Tanwir, Mansoor Wills, Rachel Perianayagam, Nidhi Wang, Peng Fiaschi-Taesch, Nathalie M. |
author_sort | Tiwari, Shiwani |
collection | PubMed |
description | Type 2 diabetes (T2D) is characterized by insulin resistance and reduced functional β-cell mass. Developmental differences, failure of adaptive expansion and loss of β-cells via β-cell death or de-differentiation have emerged as the possible causes of this reduced β-cell mass. We hypothesized that the proliferative response to mitogens of human β-cells from T2D donors is reduced, and that this might contribute to the development and progression of T2D. Here, we demonstrate that the proliferative response of human β-cells from T2D donors in response to cdk6 and cyclin D3 is indeed dramatically impaired. We show that this is accompanied by increased nuclear abundance of the cell cycle inhibitor, p27(kip1). Increasing nuclear abundance of p27(kip1) by adenoviral delivery decreases the proliferative response of β-cells from non-diabetic donors, mimicking T2D β-cells. However, while both p27(kip1) gene silencing and downregulation by Skp2 overexpression increased similarly the proliferative response of human β-cells, only Skp2 was capable of inducing a significant human β-cell expansion. Skp2 was also able to double the proliferative response of T2D β-cells. These studies define c-Myc as a central Skp2 target for the induction of cell cycle entry, expansion and regeneration of human T2D β-cells. |
format | Online Article Text |
id | pubmed-4933882 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-49338822016-07-08 Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells Tiwari, Shiwani Roel, Chris Tanwir, Mansoor Wills, Rachel Perianayagam, Nidhi Wang, Peng Fiaschi-Taesch, Nathalie M. Sci Rep Article Type 2 diabetes (T2D) is characterized by insulin resistance and reduced functional β-cell mass. Developmental differences, failure of adaptive expansion and loss of β-cells via β-cell death or de-differentiation have emerged as the possible causes of this reduced β-cell mass. We hypothesized that the proliferative response to mitogens of human β-cells from T2D donors is reduced, and that this might contribute to the development and progression of T2D. Here, we demonstrate that the proliferative response of human β-cells from T2D donors in response to cdk6 and cyclin D3 is indeed dramatically impaired. We show that this is accompanied by increased nuclear abundance of the cell cycle inhibitor, p27(kip1). Increasing nuclear abundance of p27(kip1) by adenoviral delivery decreases the proliferative response of β-cells from non-diabetic donors, mimicking T2D β-cells. However, while both p27(kip1) gene silencing and downregulation by Skp2 overexpression increased similarly the proliferative response of human β-cells, only Skp2 was capable of inducing a significant human β-cell expansion. Skp2 was also able to double the proliferative response of T2D β-cells. These studies define c-Myc as a central Skp2 target for the induction of cell cycle entry, expansion and regeneration of human T2D β-cells. Nature Publishing Group 2016-07-06 /pmc/articles/PMC4933882/ /pubmed/27380896 http://dx.doi.org/10.1038/srep28461 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Tiwari, Shiwani Roel, Chris Tanwir, Mansoor Wills, Rachel Perianayagam, Nidhi Wang, Peng Fiaschi-Taesch, Nathalie M. Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells |
title | Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells |
title_full | Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells |
title_fullStr | Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells |
title_full_unstemmed | Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells |
title_short | Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells |
title_sort | definition of a skp2-c-myc pathway to expand human beta-cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933882/ https://www.ncbi.nlm.nih.gov/pubmed/27380896 http://dx.doi.org/10.1038/srep28461 |
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