Gadd45 in the Liver: Signal Transduction and Transcriptional Mechanisms.

Injury and growth stimulation both remarkably increase the hepatic expression of Gadd45β. This contrasts with expression in liver cancer, where promoter methylation frequently silences Gadd45β, due to a suppressive function that is often proapoptotic. In normal hepatocytes, Gadd45β facilitates cell survival, growth, and proliferation. Gadd45β binds MKK7-downstream of TNFα and its receptors-to prevent this kinase from activating JNK2. Hence, the Gadd45β-/- genotype increases cell injury and decreases cell proliferation during liver regeneration (compensatory growth and proliferation). Liver hyperplasia (de novo growth and proliferation) is an alternate form of growth, caused by drugs that activate the nuclear receptor, CAR. As in regeneration, the Gadd45β-/- genotype considerably slows growth during hyperplasia. However, there is no injury and the slowing occurs because Gadd45β normally binds to CAR and activates its transcriptional stimulation. Thus, Gadd45β protects the liver through two entirely different processes: Binding MKK7 to block damaging signal transduction, or binding CAR to coactivate anabolic transcription.