<b>Dual-input regulation of</b><b> </b><b>β-cell proliferation by ATF6α and glucose via E2F1</b>

<p dir="ltr">Finding ways to increase β-cell mass is a key goal of diabetes research. During elevated insulin demand β-cells turn on ER stress response pathways, and some β-cells enter the cell cycle. ER stress response protein ATF6α induces β-cell proliferation, but only in high glucose. The mechanism by which ATF6α increases proliferation, and the reasons for glucose dependence, remain unknown. Here we show that ATF6α activation in mouse and human islet cells increases expression of E2F1, a key cell cycle driver. E2F1 was required for ATF6α-induced proliferation in high glucose. However, E2F1 remained inactive in normal glucose, possibly because Rb, a direct E2F1 inhibitor, was in its dephosphorylated, active state. Indeed, inducing Rb phosphorylation by overexpressing CDK4 allowed ATF6α to increase E2F1 activity and β-cell proliferation in normal glucose. E2F1 expression increased in ATF6α-dependent manner during generalized ER stress by thapsigargin treatment. Importantly, in human β-cells ATF6α failed to synergize with high glucose to induce proliferation, but the synergy was rescued by adding back CDK6. Taken together, this study establishes a new dual-input β-cell proliferation regulatory mechanism integrating ER load with current glycemic conditions via CDK4/6, in which Rb phosphorylation serves as a glucose sensor that permits ATF6α-driven proliferation.</p>