The role of Foxm1 in growth factor-mediated pancreatic beta-cell proliferation

Abstract

THE ROLE OF FOXM1 IN GROWTH FACTOR-MEDIATED PANCREATIC BETA-CELL PROLIFERATION

JIA ZHANG

Dissertation under the direction of Professor Maureen A. Gannon Both type I and type II diabetes are due to an either absolute or relative loss of â-cell mass. A thorough understanding of â-cell mass regulation is needed for treatment of diabetes by restoring â-cell mass and glucose homeostasis. In adults, â-cell mass is replenished mainly through â-cell proliferation. Growth factors such as placental lactogen (PL), insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF) are potent â-cell mitogens. However, little is known about the intrinsic factors within a â-cell that mediate the mitogenic effects of growth factors. In searching for those intrinsic factors, previous studies from our laboratory have demonstrated that Foxm1, a pro-proliferation transcription factor, is required for the maintenance and expansion of adult â-cell mass under basal conditions and in injury models. This dissertation examined the hypothesis that Foxm1 plays a central role downstream of one or multiple growth factors to stimulate â-cell proliferation. The pregnancy hormone PL is mainly responsible for increased â-cell proliferation in pregnancy. We found that Foxm1 was up-regulated in maternal islets during pregnancy and PL induced Foxm1 expression in cultured islets. Additionally, Foxm1 was required for PL-mediated â-cell proliferation in vivo. Our preliminary data further identified Foxm1 as a novel direct target of the transcription factor Stat5, a downstream effector of PL signaling. To determine whether Foxm1 is essential for increases in â-cell proliferation and mass during pregnancy, we evaluated female mice with a pancreas-wide Foxm1 inactivation (Foxm1Äpanc). These mice developed gestational diabetes. Compared to controls, Foxm1Äpanc mice exhibited blunted â-cell proliferation and mass in response to pregnancy, which is likely due to the elevated islet expression or activity of two cell cycle inhibitors, Menin and p27. Foxm1-mediated â-cell proliferation is thus crucial for â-cell mass expansion and glucose homeostasis during pregnancy. Our ongoing endeavors include examining whether Foxm1 is required for HGF and IGF-1-stimulated â-cell proliferation. In conclusion, the central role of Foxm1 in â-cell maintenance and growth factor stimulated-growth makes it a promising therapeutic candidate for enhancing â-cell mass in vivo.