Figure 8
From: Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells
Skp2 enhances the proliferative response of human β-cells in a c-Myc dependent manner and increases the proliferative response of T2D β-cells.
(A) Dispersed human islets from normal donors were transduced with control adenovirus (“CTL”) or with Ad.cdk6 and cyclin D3 (C6 + D3), or with Ad.cdk6 and cyclin D3 and Skp2 (C6 + D3 + skp2) and treated with or without the c-Myc inhibitor 1RH. Immunolabeling for Ki67 is shown in red, insulin in white and DAPI in blue. Experiments were repeated on at least four human islet preps. (B) Quantification of data in C at 72 hours after transduction. Bars indicate mean ± SEM of the % of the proliferation with cdk6 and cyclin D3. (C) Dispersed human islets from T2D donors were transduced with control adenovirus (“CTL”) or with Ad.cdk6 and cyclin D3 (C6 + D3), or with Ad.cdk6 and cyclin D3 and Skp2 (C6 + D3 + skp2). Quantification of the % of Ki67 in insulin + cells at 72 hours after transduction. Bars indicate mean ± SEM of the % of Ki67 in insulin + cells. Experiments were repeated on at least three human islet preps from T2D donors. (D) Schematic cartoon of the actions of Skp2 in human β-cells. Skp2 reduces the expression of p27kip1. The reduction of p27kip1 expression alone leads to an increased proliferative capacity, but not an increased in β-cells number. Skp2 also increases, directly or indirectly (as indicated by multiple arrows and a question mark), the transcriptional activity of c-Myc, inducing the expression of cyclin E1, E2, cdc25a, E2F1 and E2F3, therefore leading to an increased proliferative capacity and expansion of human β-cells in vitro.
