The c-Jun Dimerization Protein 2 Inhibits Cell Transformation and Acts as a Tumor Suppressor Gene

Ronit Heinrich,Erella Livne,Offer Ben-Izhak,Ami Aronheim

doi:10.1074/jbc.m307608200

Abstract

The c-Jun dimerization protein, JDP2, is a member of the AP-1 (activating protein-1) family of the basic leucine zipper transcription factors. JDP2 can bind 12-O-tetradecanoylphorbol-13-acetate (TPA)-responsive element and cAMP-responsive element DNA response elements, resulting in the inhibition of transcription. Although the role of AP-1 in cell proliferation and malignant transformation is well established, the role of JDP2 in this process is of subject to debate. On the one hand, JDP2 was shown to inhibit cyclin D transcription and promote differentiation of skeletal muscle and osteoclast cells. On the other hand, JDP2 was shown to partially transform chicken embryo fibroblast and was identified in a screen for oncogenes able to collaborate with the loss of p27kip cyclin-dependent inhibitor to induce lymphomas. Using cell transformation assays in NIH3T3 cells and injection of prostate cancer cell lines overexpressing JDP2 into severe combined immuno-deficient (SCID) mice, we show for the first time the potential role of JDP2 in inhibition of cell transformation and tumor suppression. The mechanism of tumor suppressor action of JDP2 can be partially explained by the generation of inhibitory AP-1 complexes via the increase of JunB, JunD, and Fra2 expression and decrease of c-Jun expression.

Highlights

The c-Jun dimerization protein, JDP2, is a member of the activating protein-1 (AP-1) family of the basic leucine zipper transcription factors
Using cell transformation assays in NIH3T3 cells and injection of prostate cancer cell lines overexpressing JDP2 into severe combined immuno-deficient (SCID) mice, we show for the first time the potential role of JDP2 in inhibition of cell transformation and tumor suppression
Inhibition of Ras Transformation in NIH3T3 Cells—The overexpression of JDP2 in chicken embryo fibroblast resulted in the loss of contact inhibitory cell growth and generation of foci characteristic of cell transformation [13]

Summary

Introduction

The c-Jun dimerization protein, JDP2, is a member of the AP-1 (activating protein-1) family of the basic leucine zipper transcription factors. JDP2 action as a tumor suppressor gene inhibits AP-1 activity through the increase of JunB, JunD, and Fra2 protein levels and decrease of c-Jun expression. Ras-transfected cells exhibited loss of contact growth inhibition and typical foci formation, cells co-transfected with RasV12 together with JDP2 exhibited a significant reduction in size, and only 16% of the number of foci formed as compared with RasV12 alone (Fig. 1, A and B), suggesting that JDP2 has a potential to serve as a tumor suppressor gene.

Results

Conclusion