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Diabetologia

Erschienen in:

01.09.2015 | Article

Prolactin-stimulated survivin induction is required for beta cell mass expansion during pregnancy in mice

verfasst von: Yili Xu, Xiaojing Wang, Li Gao, Jiayu Zhu, Hui Zhang, Houxia Shi, Minna Woo, Xiaohong Wu

Erschienen in: Diabetologia | Ausgabe 9/2015

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Abstract

Aims/hypothesis

Prolactin (PRL)-stimulated beta cell proliferation is critical for maternal pancreatic beta cell mass expansion during pregnancy. However, the molecular effectors of the multiple putative signalling pathways downstream of the PRL receptor (PRL-R) are still elusive. Survivin has been shown to be induced during pregnancy. The aim of the present study was to define the essential role of survivin in gestational beta cell mass expansion.

Methods

Expression of survivin was assessed in mouse islets during pregnancy and in insulinoma cells (INS-1) stimulated with PRL. Pregnant mice with targeted deletion of the survivin gene (also known as Birc5) in beta cells were assessed to determine the essential function of survivin in maternal beta cell mass expansion. INS-1 cells stimulated with PRL were used to explore the role of survivin in signalling pathways downstream of the PRL-R.

Results

Survivin was significantly upregulated in maternal islets during pregnancy. With PRL stimulation, induction of survivin expression occurred predominantly in the nucleus and was associated with cell cycle progression to S and G2/M phase. Beta cell-specific survivin-knockout pregnant mice displayed glucose intolerance, attenuated beta cell mass expansion and impaired beta cell proliferation, with significant attenuation in the increased expression of Cdk4/Ccnd1, E2f1, p53 (also known as Trp53) and p21 (also known as Cdkn1a) compared with wild-type controls during pregnancy. Targeted deletion of survivin in INS-1 cells resulted in cell cycle disturbance with an arrest in G1/S phase after PRL stimulation. Inhibitors of Akt, signal transducer and activator of transcription 5 (STAT5), PIM or extracellular signal-regulated kinase (ERK), significantly decreased the expression of survivin in PRL-stimulated INS-1 cells.

Conclusions/interpretation

Survivin directly participates in PRL-mediated beta cell proliferation via Akt, STAT5–PIM and ERK signalling pathways during pregnancy.

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Titel: Prolactin-stimulated survivin induction is required for beta cell mass expansion during pregnancy in mice
verfasst von: Yili Xu
Xiaojing Wang
Li Gao
Jiayu Zhu
Hui Zhang
Houxia Shi
Minna Woo
Xiaohong Wu
Publikationsdatum: 01.09.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 9/2015
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-015-3670-0

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Prolactin-stimulated survivin induction is required for beta cell mass expansion during pregnancy in mice

Abstract

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Methods

Results

Conclusions/interpretation

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