Gadd45 in the Liver: Signal Transduction and Transcriptional Mechanisms

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.

Growth arrest and DNA damage-inducible 45α protects against nonalcoholic steatohepatitis induced by methionine- and choline-deficient diet

“…It is known that Gadd45α is up-regulated in response to DNA damage [3,4]. However, while DNA damage is a consequence of various cytotoxic stimuli, it is unclear whether Gadd45α induction is the result of DNA damage.…”

“…However, while DNA damage is a consequence of various cytotoxic stimuli, it is unclear whether Gadd45α induction is the result of DNA damage. Additionally, the contribution of Gadd45α to apoptotic signaling is controversial [3,4]. Experiments using primary hepatocytes demonstrated that ER stress is an early inducer of Gadd45α.…”

“…Growth arrest and DNA damage-inducible 45 α (Gadd45α) is a 17–18 kilodalton protein that is linked to several cellular events, such as cell survival, DNA repair, chromatin assembly, and genome stability [3,4]. For example, Gadd45α is markedly induced after the administration of dimethylbenzanthracene (DMBA), a genotoxic carcinogen in mice, and decreased DNA repair, increased mutation frequency, and enhanced tumorigenesis were observed in DMBA-treated Gadd45a -null mice compared with wild-type (WT) mice [5].…”

“…For example, Gadd45α is markedly induced after the administration of dimethylbenzanthracene (DMBA), a genotoxic carcinogen in mice, and decreased DNA repair, increased mutation frequency, and enhanced tumorigenesis were observed in DMBA-treated Gadd45a -null mice compared with wild-type (WT) mice [5]. Additionally, Gadd45α is regulated by p53 and stress-responsive transcription factors, such as activating transcription factor (ATF) 2 [4,6]. These findings indicate a possible link between Gadd45α and chronic liver injury, but its contribution to the pathogenesis of NASH remains unclear.…”

GADD45β induction by S-adenosylmethionine inhibits hepatocellular carcinoma cell proliferation during acute ischemia-hypoxia

“…The level of downregulation of growth arrest DNA damage-inducible gene 45β (GADD45b) in HCC is strongly correlated with increased tumor malignancy [5]. GADD45β is associated with cell growth control, apoptosis and cellular responses to DNA damage [6]. Consequently, lack of GADD45β expression in HCC might lead to atypical cell growth or apoptosis.…”