Role of tyrosine kinase signaling in estrogen-induced LDL receptor gene expression in HepG2 cells.

The expression of the low-density lipoprotein receptor (LDL-r) gene is stimulated by estrogen in vivo, although its promoter does not contain a classical estrogen-responsive element, suggesting an alternative mechanism of estrogen-regulated expression of this gene. The aim of this work was to assess whether estrogen-stimulated transcription of the LDL-r gene depends on tyrosine kinase (TK) and protein kinase C (PKC) activation, both signaling pathways being activated by estrogen in vivo and in hepatoma cells. Therefore, in HepG2 cells cotransfected with estrogen receptor-alpha, estrogen-stimulated transcription of LDL-r-promoter reporter plasmid was analyzed in the absence and presence of TK and PKC inhibitors. The expression of LDL-r was also compared with the transcription of the complement gene, which contains a classical estrogen-responsive element sequence. Our results demonstrate that the induction of LDL-r expression by estrogen requires longer stimulation than that necessary for complement induction. Moreover, basal transcription of the LDL-r gene depends on PKC activity, while estrogen-stimulated activation of the LDL-r-promoter requires TK activity, pointing to a role of these non-classical estrogen-stimulated pathways in the transcriptional regulation of the LDL-r.