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. 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 signal transducer and activator of transcription 5 (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 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, 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. It appears that PRL promotes Rb phosphorylation and E2F1 upregulation via STAT5-CyclinD/CDK4 pathway during pregnancy.

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