? The overall goal of our research is to determine the molecular regulation of adult beta-cell proliferation. We recently discovered that cyclin D2 is the major D-type cyclin in beta-cells, and is essential for adult beta-cell growth. Cyclin D2 must promote cell cycle progression in beta-cells by activating cyclin dependent kinase-4 to phosphorylate downstream targets. Moreover, our new preliminary evidence strongly suggests that the """"""""pocket proteins"""""""" (pRb/p107/p130) are downstream to regulate (-cell proliferation: Acute deletion of Rb in adult (-cells stimulates proliferation ~3 fold. Although this significant result reinforces the important role of pRb, 85% of adult (-cells failed to proliferate by two weeks despite acute Rb deficiency. Thus, other factors must limit (-cell proliferation. p130 (a.k.a. pRb2) is an attractive candidate, as it maintains some cells in a quiescent (G0) state. Based on preliminary data, we hypothesize that p130 critically regulates beta cell proliferation. Here, we propose hypothesis-driven studies to genetically interrogate p130 dependent regulation of beta-cell proliferation. Thus, the following specific aims: 1. Determine the role of p130 in beta-cell proliferation; 2. Investigate the hypothesis that p130 and pRb have synergistic effects to restrict beta-cell proliferation. Our past studies reveal that cyclin D2, in particular, has an essential role to control cell cycle progression of beta-cells. Thus, the studies contained within this proposal represent a unique opportunity to determine the molecular regulation of beta-cell proliferation, towards the goal of regeneration of beta-cell function. Improved understanding of beta-cell growth is an important goal that could benefit patients with type 1 or type 2 diabetes, allowing preservation of insulin secretion in patients with type 2 diabetes, or expansion of islets for transplant into patients with type 1 diabetes. Here, we propose studies to genetically interrogate the role of p130, a key component in cell division, in beta-cell growth. ? ?
| He, Lu Mei; Sartori, Daniel J; Teta, Monica et al. (2009) Cyclin D2 protein stability is regulated in pancreatic beta-cells. Mol Endocrinol 23:1865-75 |
| Rankin, Matthew M; Kushner, Jake A (2009) Adaptive beta-cell proliferation is severely restricted with advanced age. Diabetes 58:1365-72 |
