Tcf19 is a novel islet factor necessary for proliferation and survival in the INS-1 β-cell line

Abstract

Recently, a novel type 1 diabetes association locus was identified at human chromosome 6p31.3, and transcription factor 19 (TCF19) is a likely causal gene. Little is known about Tcf19, and we now show that it plays a role in both proliferation and apoptosis in insulinoma cells. Tcf19 is expressed in mouse and human islets, with increasing mRNA expression in nondiabetic obesity. The expression of Tcf19 is correlated with β-cell mass expansion, suggesting that it may be a transcriptional regulator of β-cell mass. Increasing proliferation and decreasing apoptotic cell death are two strategies to increase pancreatic β-cell mass and prevent or delay diabetes. siRNA-mediated knockdown of Tcf19 in the INS-1 insulinoma cell line, a β-cell model, results in a decrease in proliferation and an increase in apoptosis. There was a significant reduction in the expression of numerous cell cycle genes from the late G1 phase through the M phase, and cells were arrested at the G1/S checkpoint. We also observed increased apoptosis and susceptibility to endoplasmic reticulum (ER) stress after Tcf19 knockdown. There was a reduction in expression of genes important for the maintenance of ER homeostasis (Bip, p58IPK, Edem1, and calreticulin) and an increase in proapoptotic genes (Bim, Bid, Nix, Gadd34, and Pdia2). Therefore, Tcf19 is necessary for both proliferation and survival and is a novel regulator of these pathways.

Expression and functional assessment of candidate type 2 diabetes susceptibility genes identify four new genes contributing to human insulin secretion

“…In contrast, insulin secretion from EndoC-βH1 cells was significantly changed by the decreased expression of five T2D susceptibility genes already suggested to be expressed and/or to contribute to beta-cell function [19], [20], [21], [22], [23]: the knockdown of TCF19 was found to significantly decrease GSIS ( p  < 0.01; Figure 4A); the decreased expression of SLC30A8 affected GSIS evoked or not by IBMX ( p  < 0.05; Figure 4B); the knockdown of TBC1D4 was found to significantly reduce GSIS evoked by IBMX ( p  < 0.01; Figure 4C); the decreased expression of CDKN2A was found to decrease GSIS evoked by IBMX ( p  < 0.01; Figure 4D); and the knockdown of KCNK16 was found to stimulate GSIS evoked by IBMX ( p  < 0.05; Figure 4E).

Figure 4 Decreased expression of TCF19 (A), SLC30A8 (B), TBC1D4 (C), CDKN2A (D), or KCNK16 (E), already suggested to be expressed in beta cell and/or to contribute to beta-cell function, significantly modifies insulin secretion from EndoC-βH1 cells . EndoC-βH1 cells were transfected with control non-targeting pool siRNA (siNTP) or target gene siRNA and were analyzed 72 h post-transfection.

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TCF19 enhances cell proliferation in hepatocellular carcinoma by activating the ATK/FOXO1 signaling pathway

“…It has been documented that TCF19 over-expression enhances the cell proliferation in insulinoma cells [17]. So we further explored whether TCF19 has the same impact on HCC cell proliferation by selecting the HepG2 cell which moderately expresses TCF19 for gain-and-loss-of-function assay.…”

Pancreatic β-Cell Proliferation in Obesity

“…Differential genetic regulation of b-cell replication may explain the strain-specific differences in b-cell adaptive proliferation. In fact, differential expression of several key cell cycle genes important in b-cell proliferation has been found between these 2 strains (15,25,26).…”