title: Augmented Stat5 Signaling Bypasses Multiple Impediments to Lactogen-Mediated Proliferation in Human β-Cells.
abstract: Pregnancy in rodents is associated with a two- to threefold increase in β-cell mass, which is attributable to large increases in β-cell proliferation, complimented by increases in β-cell size, survival, and function and mediated mainly by the lactogenic hormones prolactin (PRL) and placental lactogens. In humans, however, β-cell mass does not increase as dramatically during pregnancy, and PRL fails to activate proliferation in human islets in vitro. To determine why, we explored the human PRL-prolactin receptor (hPRLR)-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5)-cyclin-cdk signaling cascade in human β-cells. Surprisingly, adult human β-cells express little or no PRLR. As expected, restoration of the hPRLR in human β-cells rescued JAK2-STAT5 signaling in response to PRL. However, rescuing hPRLR-STAT5 signaling nevertheless failed to confer proliferative ability on adult human β-cells in response to PRL. Surprisingly, mouse (but not human) Stat5a overexpression led to upregulation of cyclins D1-3 and cdk4, as well as their nuclear translocation, all of which are associated with β-cell cycle entry. Collectively, the findings show that human β-cells fail to proliferate in response to PRL for multiple reasons, one of which is a paucity of functional PRL receptors, and that murine Stat5 overexpression is able to bypass these impediments.
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY hainanchen2011@gmail.com andrew.stewart@mssm.edu.
authors.forename: Hainan
authors.initials: H
authors.lastname: Chen
authors.affiliation: University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Kleinberger
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Takane
authors.affiliation: Duquesne University School of Nursing, Pittsburgh, PA.
authors.forename: Fatimah
authors.initials: F
authors.lastname: Salim
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Fiaschi-Taesch
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Kyrie
authors.initials: K
authors.lastname: Pappas
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Ramon
authors.initials: R
authors.lastname: Parsons
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Jing
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Bender
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL Endocrinology Section, Birmingham VA Medical Center, Birmingham, AL.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Frank
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY hainanchen2011@gmail.com andrew.stewart@mssm.edu.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Stewart
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011388:Prolactin / Q000494:pharmacology*; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation
chemical_list: D056741:Cyclin D; D011981:Receptors, Prolactin; D050799:STAT5 Transcription Factor; D011388:Prolactin; D051358:Cyclin-Dependent Kinase 4