title: cMyc is a principal upstream driver of beta-cell proliferation in rat insulinoma cell lines and is an effective mediator of human beta-cell replication.
abstract: Adult human β-cells replicate slowly. Also, despite the abundance of rodent β-cell lines, there are no human β-cell lines for diabetes research or therapy. Prior studies in four commonly studied rodent β-cell lines revealed that all four lines displayed an unusual, but strongly reproducible, cell cycle signature: an increase in seven G(1)/S molecules, i.e. cyclins A, D3, and E, and cdk1, -2, -4, and -6. Here, we explore the upstream mechanism(s) that drive these cell cycle changes. Using biochemical, pharmacological and molecular approaches, we surveyed potential upstream mitogenic signaling pathways in Ins 1 and RIN cells. We used both underexpression and overexpression to assess effects on rat and human β-cell proliferation, survival and cell cycle control. Our results indicate that cMyc is: 1) uniquely up-regulated among other candidates; 2) principally responsible for the increase in the seven G(1)/S molecules; and, 3) largely responsible for proliferation in rat β-cell lines. Importantly, cMyc expression in β-cell lines, although some 5- to 7-fold higher than normal rat β-cells, is far below the levels (75- to 150-fold) previously associated with β-cell death and dedifferentiation. Notably, modest overexpression of cMyc is able to drive proliferation without cell death in normal rat and human β-cells. We conclude that cMyc is an important driver of replication in the two most commonly employed rat β-cell lines. These studies reverse the current paradigm in which cMyc overexpression is inevitably associated with β-cell death and dedifferentiation. The cMyc pathway provides potential approaches, targets, and tools for driving and sustaining human β-cell replication.
authors: Division of Endocrinology, the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
authors: Esra
authors: E
authors: Karslioglu
authors: Jeffrey W
authors: JW
authors: Kleinberger
authors: Fatimah G
authors: FG
authors: Salim
authors: Amy E
authors: AE
authors: Cox
authors: Karen K
authors: KK
authors: Takane
authors: Donald K
authors: DK
authors: Scott
authors: Andrew F
authors: AF
authors: Stewart
mesh_terms: D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D007340:Insulinoma / Q000235:genetics / Q000473:pathology*; D008954:Models, Biological; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016196:S Phase; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger