The AP-1 repressor protein, JDP2, potentiates hepatocellular carcinoma in mice

Eli Pikarsky,Ami Aronheim,Keren Bitton-Worms

doi:10.1186/1476-4598-9-54

Abstract

BackgroundThe AP-1 transcription factor plays a major role in cell proliferation, apoptosis, differentiation and developmental processes. AP-1 proteins are primarily considered to be oncogenic. Gene disruption studies placed c-Jun as an oncogene at the early stage of a mouse model of hepatocellular carcinoma. Mice lacking c-Jun display reduced number and size of hepatic tumors attributed to elevated p53 expression and increased apoptosis. This suggests that c-Jun inhibition may serve as a therapeutic target for liver cancer. The c-Jun dimerization protein 2, JDP2 is an AP-1 repressor protein that potently inhibits AP-1 transcription. On the other hand, the JDP2 locus was found at a recurring viral integration site in T-cell lymphoma. We sought to examine the potential of JDP2 to inhibit c-Jun/AP-1 oncogenic activity in mice. Towards this end, we generated a tetracycline inducible transgenic mouse expressing JDP2 specifically in the liver. We used diethylnitrosamine (DEN) injection to initiate liver cancer in mice and assessed the extent of liver cancer in JDP2-transgenic and wild type control mice by biochemical and molecular biology techniques.ResultsJDP2-transgenic mice display normal liver function. JDP2-transgenic mice displayed potentiation of liver cancer, higher mortality and increased number and size of tumors. The expression of JDP2 at the promotion stage was found to be the most critical for enhancing liver cancer severity.ConclusionsThis study suggests that JDP2 expression may play a critical role in liver cancer development by potentiating the compensatory proliferative response and increased inflammation in the DEN liver cancer model.

Highlights

The AP-1 transcription factor plays a major role in cell proliferation, apoptosis, differentiation and developmental processes
We found that JDP2 increases liver cancer severity and that JDP2 expression at the promotion stage is most important for this activity
To study the HA-JDP2 specific expression in the liver, JDP2-transgenic mice were sacrificed and lysates derived from different tissues were separated by SDS-PAGE followed by Western blotting with either anti-HA or antiJDP2 antibodies (Figure 1C)

Summary

Introduction

The AP-1 transcription factor plays a major role in cell proliferation, apoptosis, differentiation and developmental processes. Gene disruption studies placed c-Jun as an oncogene at the early stage of a mouse model of hepatocellular carcinoma. Mice lacking c-Jun display reduced number and size of hepatic tumors attributed to elevated p53 expression and increased apoptosis. This suggests that c-Jun inhibition may serve as a therapeutic target for liver cancer. We sought to examine the potential of JDP2 to inhibit c-Jun/AP-1 oncogenic activity in mice. Towards this end, we generated a tetracycline inducible transgenic mouse expressing JDP2 in the liver. Various mouse models for HCC were developed to study the molecular mechanisms involved in various stages of liver cancer [5].

Methods

Results

Discussion

Conclusion