An Rb family-independent E2F3 transcription factor variant impairs STAT5 signaling and mammary gland remodeling during pregnancy in mice

作者：Liao Yang; Du Wei^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2018, 293(9): 3156-3167.

DOI：10.1074/jbc.RA117.000583

E2F transcription factors are regulated by binding to the retinoblastoma (Rb) tumor suppressor family of proteins. Previously, we reported an E2F(LQ) mutation that disrupts the binding with Rb proteins without affecting the transcriptional activity of E2F. We also showed that mouse embryonic fibroblasts with an E2F3(LQ) mutation exhibit increased E2F activity and more rapid cell proliferation. In this report, we analyzed E2F3(LQ) mice to further characterize the in vivo consequences of Rb family-independent E2F3 activity. We found that homozygous E2F3(LQ) mice were viable and had no obvious developmental defects or tumor growth. Our results also indicated that E2F3(LQ) cells largely retain normal control of cell proliferation in vivo. However, female E2F3(LQ) mice had partial nursing defects. Examination of the E2F3(LQ) mammary glands revealed increased caveolin-1 (CAV1) expression, reduced prolactin receptor/Stat5 signaling, and impaired pregnancy-induced cell proliferation and differentiation. Of note, ChIP experiments disclosed that E2F3 binds the CAV1 promoter. Furthermore, E2F3 overexpression induced CAV1 expression, and CRISPR/CAS9-mediated E2F3 knockout reduced CAV1 levels and also increased prolactin receptor-induced Stat5 signaling in mammary epithelial cells. Our results suggest that the Rb family-independent E2F3(LQ) variant inhibits pregnancy-induced mammary gland cell proliferation and differentiation by up-regulating CAV1 expression and inhibiting Stat5 signaling.

• 出版日期2018-3-2