Involvement of the STAT5-cyclin D/CDK4-pRb pathway in ß-cell proliferation stimulated by prolactin during pregnancy.
Am J Physiol Endocrinol Metab
; 316(1): E135-E144, 2019 01 01.
Article
in En
| MEDLINE
| ID: mdl-30512986
ABSTRACT
During pregnancy, maternal pancreatic ß-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 ß-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 ß-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 ß-cell mass and proliferation to wild-type pregnant controls, supporting the essential role of Rb suppression in augmenting ß-cell proliferation during pregnancy. Rb-E2F1 regulation plays a pivotal role in PRL-stimulated ß-cell proliferation. PRL promotes Rb phosphorylation and E2F1 upregulation via STAT5-cyclin D/CDK4 pathway during pregnancy.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pregnancy
/
Retinoblastoma Protein
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Cell Proliferation
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Insulin-Secreting Cells
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Cyclin-Dependent Kinase 4
/
Cyclin D
Limits:
Animals
Language:
En
Journal:
Am J Physiol Endocrinol Metab
Journal subject:
ENDOCRINOLOGIA
/
FISIOLOGIA
/
METABOLISMO
Year:
2019
Type:
Article
Affiliation country:
China