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The liver-enriched transcription factor CREB-H is a growth suppressor protein underexpressed in hepatocellular carcinoma.

ABSTRACT: We have previously characterized transcription factor LZIP to be a growth suppressor targeted by hepatitis C virus oncoprotein. In search of proteins closely related to LZIP, we have identified a liver-enriched transcription factor CREB-H. LZIP and CREB-H represent a new subfamily of bZIP factors. CREB-H activates transcription by binding to cAMP responsive element, box B, and ATF6-binding element. Interestingly, CREB-H has a putative transmembrane (TM) domain and it localizes ambiently to the endoplasmic reticulum. Proteolytic cleavage that removes the TM domain leads to nuclear translocation and activation of CREB-H. CREB-H activates the promoter of hepatic gluconeogenic enzyme phosphoenolpyruvate carboxykinase. This activation can be further stimulated by cAMP and protein kinase A. CREB-H transcript is exclusively abundant in adult liver. In contrast, the expression of CREB-H mRNA is aberrantly reduced in hepatoma tissues and cells. The enforced expression of CREB-H suppresses the proliferation of cultured hepatoma cells. Taken together, our findings suggest that the liver-enriched bZIP transcription factor CREB-H is a growth suppressor that plays a role in hepatic physiology and pathology.

SUBMITTER: Chin KT

PROVIDER: S-EPMC1072803 | biostudies-literature | 2005

REPOSITORIES: biostudies-literature

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The liver-enriched transcription factor CREB-H is a growth suppressor protein underexpressed in hepatocellular carcinoma.

Chin King-Tung KT Zhou Hai-Jun HJ Wong Chun-Ming CM Lee Joyce Man-Fong JM Chan Ching-Ping CP Qiang Bo-Qin BQ Yuan Jian-Gang JG Ng Irene Oi-lin IO Jin Dong-Yan DY

Nucleic acids research 20050330 6

We have previously characterized transcription factor LZIP to be a growth suppressor targeted by hepatitis C virus oncoprotein. In search of proteins closely related to LZIP, we have identified a liver-enriched transcription factor CREB-H. LZIP and CREB-H represent a new subfamily of bZIP factors. CREB-H activates transcription by binding to cAMP responsive element, box B, and ATF6-binding element. Interestingly, CREB-H has a putative transmembrane (TM) domain and it localizes ambiently to the e ...[more]

PMID: 15800215

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Project description:The mechanisms by which the liver fails in end-stage liver disease remain elusive. Disruption of the transcription factor network in hepatocytes has been suggested to mediate terminal liver failure in animals. However, this hypothesis remains unexplored in human subjects. To study the relevance of transcription factor expression in terminal stages of chronic liver failure in humans, we analyzed the expression of liver-enriched transcription factors (LETFs) hepatocyte nuclear factor (HNF)4?, HNF1?, forkhead box protein A2 (FOXA2), CCAAT/enhancer-binding protein (CEBP)?, and CEBP?. We then selected downstream genes responsible for some hepatic functions (ornithine transcarbamylase [OTC], cytochrome P450 3A4 [CYP3A4], coagulation factor VII [F7], cadherin 1 [CDH1], phospho-ezrin (Thr567)/radixin (Thr564)/moesin (Thr558) [p-ERM], phospho-myosin light chain [p-MLC], low-density lipoprotein receptor-related protein 1 [LRP1]) in liver tissue from patients at different stages of decompensated liver function based upon Child-Pugh classification, Model for End-Stage Liver Disease score, and degree of inflammatory activity/fibrosis. We first examined differential expression of LETF and determined whether a relationship exists between transcript and protein expression, and liver function. We found HNF4? expression was down-regulated and correlated well with the extent of liver dysfunction (P = 0.001), stage of fibrosis (P = 0.0005), and serum levels of total bilirubin (P = 0.009; r = 0.35), albumin (P < 0.001; r = 0.52), and prothrombin time activity (P = 0.002; r = 0.41). HNF4? expression also correlated with CYP3A4, OTC, and F7 as well as CDH1 RNA levels. The Rho/Rho-associated protein kinase pathways, which have been implicated in the regulation of HNF4?, were also differentially expressed, in concert with LRP1, a reported upstream regulator of RhoA function. Conclusion: HNF4? and other members of the LETFs appear to be important regulators of hepatocyte function in patients with chronic hepatic failure. (Hepatology Communications 2018;2:582-594).

Dataset Information

The liver-enriched transcription factor CREB-H is a growth suppressor protein underexpressed in hepatocellular carcinoma.

Publications

The liver-enriched transcription factor CREB-H is a growth suppressor protein underexpressed in hepatocellular carcinoma.

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