RETINOID-INDUCED APOPTOSIS AND PROLIFERATION OF HEPATOCYTES ARE MEDIATED BY DISTINCT NUCLEAR RECEPTORS

Abstract

Retinoids, derivatives of vitamin A, are important signaling molecules regulating cellular homeostasis including differentiation, apoptosis, and proliferation. In this dissertation, we examined the versatile effects of retinoids on human liver cell lines and mouse livers by genetic and biochemical approaches. The overall finding is that retinoids can cause opposing effects in liver cells. These effects are retinoid-specific, mediated by distinct nuclear receptors, and depend on intrinsic cellular settings. The first part of this dissertation studies the mechanism underlying the differential susceptibilities of human liver cancer cells to the apoptotic effect of a synthetic retinoid, fenretinide. The findings establish a role for the nuclear receptors RARβ; and Nur77 in mediating fenretinide effect. The second part of this dissertation investigates the mechanism responsible for 13-cis retinoic acid-induced liver cell proliferation. The results demonstrate that the activation of a signaling cascade PPARβ;/PDK-1/Akt is responsible for 13-cis retinoic acid-induced proliferation of liver cells.