Gadd45 in the Liver: Signal Transduction and Transcriptional Mechanisms

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


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.


Liver Regeneration Partial Hepatectomy Constitutive Androstane Receptor Transcriptional Mechanism Gadd45 Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Constitutive androstane receptor


Growth arrest and DNA damage-inducible 45 proteins


Hepatocellular carcinoma


Hepatitis C virus


Interleukin 6


c-Jun N-terminal kinase


MAPK kinase 4/JNK kinase 1


MAPK kinase 7/JNK kinase 2


Nuclear factor kappa B


Partial hepatectomy




Tumor necrosis factor alpha


Tumor necrosis factor a receptor 1, 2


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© Springer Science+Business Media New York 2013

Authors and Affiliations

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

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