Salas Elisabet, Rabhi Nabil, Froguel Philippe, Annicotte Jean-Sébastien
European Genomic Institute for Diabetes (EGID), CNRS UMR 8199, Lille 2 University, 59000 Lille, France.
European Genomic Institute for Diabetes (EGID), CNRS UMR 8199, Lille 2 University, 59000 Lille, France ; Department of Genomics of Common Disease, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
J Diabetes Res. 2014;2014:873679. doi: 10.1155/2014/873679. Epub 2014 Feb 6.
The ARF/INK4A (Cdkn2a) locus includes the linked tumour suppressor genes p16INK4a and p14ARF (p19ARF in mice) that trigger the antiproliferative activities of both RB and p53. With beta cell self-replication being the primary source for new beta cell generation in adult animals, the network by which beta cell replication could be increased to enhance beta cell mass and function is one of the approaches in diabetes research. In this review, we show a general view of the regulation points at transcriptional and posttranslational levels of Cdkn2a locus. We describe the molecular pathways and functions of Cdkn2a in beta cell cycle regulation. Given that aging reveals increased p16Ink4a levels in the pancreas that inhibit the proliferation of beta cells and decrease their ability to respond to injury, we show the state of the art about the role of this locus in beta cell senescence and diabetes development. Additionally, we focus on two approaches in beta cell regeneration strategies that rely on Cdkn2a locus negative regulation: long noncoding RNAs and betatrophin.
ARF/INK4A（Cdkn2a）基因座包含相连的肿瘤抑制基因p16INK4a和p14ARF（小鼠中的p19ARF），它们可触发RB和p53的抗增殖活性。由于β细胞自我复制是成年动物新β细胞产生的主要来源，因此增加β细胞复制以增强β细胞数量和功能的网络是糖尿病研究的方法之一。在本综述中，我们展示了Cdkn2a基因座在转录和翻译后水平调控点的总体情况。我们描述了Cdkn2a在β细胞周期调控中的分子途径和功能。鉴于衰老显示胰腺中p16Ink4a水平升高，抑制β细胞增殖并降低其对损伤的反应能力，我们展示了该基因座在β细胞衰老和糖尿病发展中作用的最新研究状况。此外，我们关注β细胞再生策略中依赖Cdkn2a基因座负调控的两种方法：长链非编码RNA和β-促胰岛素分泌素。
