Toxin and virus induced liver injury resulting in the loss of hepatic tissue, triggers a regenerative response o restore liver cell mass. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor functionally identified with proliferative processes. The AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is he prototype for a class of compounds responsible for a range of toxic or adaptive endpoints. The underlying mechanism responsible for TCDD toxicity remains poorly defined, but appears to reflect disruptions in normal cell proliferation and differentiation. Our long-term goal is to understand mechanistically how the AhR contributes to liver homeostasis by regulating cell proliferation, and to identify the molecular basis for TCDD toxicity. We have identified a component critical for AhR function: the Retinoblastoma tumor suppressor protein (pRb). Our evidence suggests that pRb may be a coactivator in AhR signaling during TCDD induced G1 phase cell cycle arrest in cultured liver cells. We hypothesize that the AhR plays an important role in liver homeostasis, in part by regulating cell proliferation via a process dependent on the AhR-pRb interaction. The goal of this proposal is to functionally characterize the AhR-pRb interaction, and to examine the AhR's role in liver regeneration in vivo.
Aim 1 will determine whether TCDD induced cell cycle arrest requires a transcriptionally competent A1IR complex comprising the AhR/Arnt protein dimer, by testing the effect of targeted mutations on AhR mediated G1 arrest.
Aim 2 will functionally characterize the AhR-pRb interaction. Studies will examine the importance of AhR coactivation by pRb and related proteins, the precise nature of the AhR-pRb interaction, and the effect of pRb phosphorylation on AhR activity.
Aim 3 will examine how the AhR contributes to cell cycle control in vivo during liver regeneration induced by partial hepatectomy. Studies will investigate the effects of TCDD and AhR mutations using adenovirus-mediated gene transfer, on in vivo liver regeneration in AhR, p27Kipl and p21Cip1 nullizygous mice, and the congenic wild-type mice.
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