title: Cytoplasmic-nuclear trafficking of G1/S cell cycle molecules and adult human β-cell replication: a revised model of human β-cell G1/S control.
abstract: Harnessing control of human β-cell proliferation has proven frustratingly difficult. Most G1/S control molecules, generally presumed to be nuclear proteins in the human β-cell, are in fact constrained to the cytoplasm. Here, we asked whether G1/S molecules might traffic into and out of the cytoplasmic compartment in association with activation of cell cycle progression. Cdk6 and cyclin D3 were used to drive human β-cell proliferation and promptly translocated into the nucleus in association with proliferation. In contrast, the cell cycle inhibitors p15, p18, and p19 did not alter their location, remaining cytoplasmic. Conversely, p16, p21, and p27 increased their nuclear frequency. In contrast once again, p57 decreased its nuclear frequency. Whereas proliferating β-cells contained nuclear cyclin D3 and cdk6, proliferation generally did not occur in β-cells that contained nuclear cell cycle inhibitors, except p21. Dynamic cytoplasmic-nuclear trafficking of cdk6 was confirmed using green fluorescent protein-tagged cdk6 and live cell imaging. Thus, we provide novel working models describing the control of cell cycle progression in the human β-cell. In addition to known obstacles to β-cell proliferation, cytoplasmic-to-nuclear trafficking of G1/S molecules may represent an obstacle as well as a therapeutic opportunity for human β-cell expansion.
authors.affiliation: Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. nmt2@pitt.edu
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Fiaschi-Taesch
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Kleinberger
authors.forename: Fatimah G
authors.initials: FG
authors.lastname: Salim
authors.forename: Ronnie
authors.initials: R
authors.lastname: Troxell
authors.forename: Rachel
authors.initials: R
authors.lastname: Wills
authors.forename: Mansoor
authors.initials: M
authors.lastname: Tanwir
authors.forename: Gabriella
authors.initials: G
authors.lastname: Casinelli
authors.forename: Amy E
authors.initials: AE
authors.lastname: Cox
authors.forename: Karen K
authors.initials: KK
authors.lastname: Takane
authors.forename: Harish
authors.initials: H
authors.lastname: Srinivas
authors.forename: Donald K
authors.initials: DK
authors.lastname: Scott
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Stewart
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002648:Child; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D005260:Female; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D016196:S Phase / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins