title: Role of Ink4a/Arf locus in beta cell mass expansion under physiological and pathological conditions.
abstract: 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.
authors.affiliation: European Genomic Institute for Diabetes (EGID), CNRS UMR 8199, Lille 2 University, 59000 Lille, France.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Salas
authors.affiliation: European Genomic Institute for Diabetes (EGID), CNRS UMR 8199, Lille 2 University, 59000 Lille, France.
authors.forename: Nabil
authors.initials: N
authors.lastname: Rabhi
authors.affiliation: 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.
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.affiliation: European Genomic Institute for Diabetes (EGID), CNRS UMR 8199, Lille 2 University, 59000 Lille, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Annicotte
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D048429:Cell Size; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology; D056426:Genetic Loci; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D010179:Pancreas / Q000293:injuries / Q000502:physiology / Q000503:physiopathology; D012038:Regeneration; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF