title: Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells.
abstract: 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.
authors.affiliation: Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Shiwani
authors.initials: S
authors.lastname: Tiwari
authors.affiliation: Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Roel
authors.affiliation: The Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
authors.forename: Mansoor
authors.initials: M
authors.lastname: Tanwir
authors.affiliation: The Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Wills
authors.affiliation: Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Perianayagam
authors.affiliation: Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.|The Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Fiaschi-Taesch
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D056743:Cyclin D3 / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D056743:Cyclin D3; D007328:Insulin; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6