| First Author | Zhao X | Year | 2019 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 316 |
| Issue | 1 | Pages | E135-E144 |
| PubMed ID | 30512986 | Mgi Jnum | J:274404 |
| Mgi Id | MGI:6283266 | Doi | 10.1152/ajpendo.00242.2018 |
| Citation | Zhao X, et al. (2019) Involvement of the STAT5-cyclin D/CDK4-pRb pathway in beta-cell proliferation stimulated by prolactin during pregnancy. Am J Physiol Endocrinol Metab 316(1):E135-E144 |
| abstractText | During pregnancy, maternal pancreatic beta-cells undergo a compensatory expansion in response to the state of insulin resistance, where prolactin (PRL) plays a major role. Retinoblastoma protein (Rb) has been shown to critically regulate islet proliferation and function. The aim of the study was to explore the role of Rb in beta-cell mass expansion during pregnancy. Expression of pocket protein family and E2Fs were examined in mouse islets during pregnancy and in insulinoma cells (INS-1) stimulated by PRL. PRL-stimulated INS-1 cells were used to explore the signaling pathway that regulates Rb downstream of the PRL receptor. Pancreas-specific Rb-knockout (Rb-KO) mice were assessed to evaluate the in vivo function of Rb in beta-cell proliferation during pregnancy. During pregnancy, expression of Rb, phospho-Rb (p-Rb), p107, and E2F1 increased, while p130 decreased in maternal islets. With PRL stimulation, induction of Rb expression occurred mainly in the nucleus, while p-Rb was predominantly in the cytoplasm. Inhibition of STAT5 significantly restrained the expression of CDK4, Rb, p-Rb, and E2F1 in PRL-stimulated INS-1 cells with attenuation in cell cycle progression. Reduction of Rb phosphorylation by CDK4 inhibition blocked PRL-mediated proliferation of INS-1 cells. On the other hand, knockdown of Rb using siRNA led to an induction in E2F1 leading to cell cycle progression from G1 to S and G2/M phase, similar to the effects of PRL-mediated induction of p-Rb that led to cell proliferation. With Rb knockdown, PRL did not lead to further increase in cell cycle progression. Similarly, while Rb-KO pregnant mice displayed better glucose tolerance and higher insulin secretion, they had similar beta-cell mass and proliferation to wild-type pregnant controls, supporting the essential role of Rb suppression in augmenting beta-cell proliferation during pregnancy. Rb-E2F1 regulation plays a pivotal role in PRL-stimulated beta-cell proliferation. PRL promotes Rb phosphorylation and E2F1 upregulation via STAT5-cyclin D/CDK4 pathway during pregnancy. |
