Gadd45 in the Liver: Signal Transduction and Transcriptional Mechanisms

Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 793)

Abstract

Injury and growth stimulation both remarkably increase the hepatic expression of Gadd45β. In liver cancer, promoter methylation frequently silences Gadd45β, demonstrating due to a suppressive function that is often proapoptotic. This contrasts with normal hepatocytes, where 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 Gadd45b−/− genotype increases cell injury and decreases cell proliferation during liver regeneration (i.e., compensatory growth and proliferation). Liver hyperplasia (i.e., de novo growth and proliferation) is an alternate form of growth, caused by drugs that activate the nuclear receptor, CAR. As in regeneration, the Gadd45b−/− 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.

Keywords

Hepatitis Ischemia Carbohydrate Benzene Hydrocarbon 

Abbreviations

CAR

Constitutive androstane receptor

Gadd45

Growth arrest and DNA damage-inducible 45 proteins

HCC

Hepatocellular carcinoma

HCV

Hepatitis C virus

IL6

Interleukin 6

JNK

c-Jun N-terminal kinase

MKK4/JNKK1

MAPK kinase 4/JNK kinase 1

MKK7/JNKK2

MAPK kinase 7/JNK kinase 2

NFκB

Nuclear factor kappa B

PH

Partial hepatectomy

TCPOBOP

1,4-bis[2-(3,5-dichloropyridyloxy)]benzene

TNFα

Tumor necrosis factor alpha

TNFR1, TNFR2

Tumor necrosis factor a receptor 1, 2

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghUSA

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