Partial oncogenic transformation of chicken embryo fibroblasts by Jun dimerization protein 2, a negative regulator of TRE- and CRE-dependent transcription

Abstract

Jun dimerization protein 2 (JDP2) was identified as a bZIP protein that forms dimers with Jun proteins. JDP2 represses transcriptional activation of reporter constructs containing 12-O-tetradecanoylphorbol 13-acetate (TPA)-responsive elements (TRE) or cyclic AMP responsive elements (CRE). JDP2, overexpressed by the avian retroviral vector RCAS, induces partial oncogenic transformation of chicken embryo fibroblasts. JDP2-expressing cells form multilayered foci in monolayer cultures but do not show anchorage-independent growth. Both the carboxyl and the amino terminus of JDP2 are required for the transforming activity. Chimeric constructs of JDP2 carrying the leucine zipper domain of Fos, GCN4 or EB1 fail to transform CEF. The leucine zipper of Fos mediates only heterodimerization; it cannot homodimerize. In contrast, the leucine zippers of GCN4 and of EB1 exclusively homodimerize and do not form dimers with other bZip proteins. The results with the JDP2 chimeras suggest that the JDP2 homodimer and the JDP2/Jun heterodimer (or other bZip heterodimers formed with the Fos leucine zipper) are nontransforming, leaving as possible transforming combination the JDP2/Fos heterodimer. The unexpected transforming activity of a negative regulator of TRE-and CRE-dependent transcription raises an important question concerning the mechanisms of transformation by the related bZIP proteins Jun and Fos that address the same target sequences.

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

“…Although JDP2 efficiently counteracts AP-1 action (3), it was identified as a candidate oncogene in a high throughput viral insertional mutagenesis screen collaborating with p27 kip loss of function mutation (12). Consistent with this result, JDP2 was found to transform chicken embryo fibroblast but failed to induce anchorage-independent growth in these cells (13). Here we show that JDP2 overexpression in NIH3T3 cells inhibits cell transformation by Ras.…”

IRF2‐binding protein‐1 is a JDP2 ubiquitin ligase and an inhibitor of ATF2‐dependent transcription

“…4B, columns 2-5). When JDP2 was expressed at a level that partially inhibited ATF2-dependent activation (column 9), IRF2-BP1 still repressed transcription (columns [10][11][12], and the relative extents of repression were similar to those in the absence of JDP2 (columns 3-5). Therefore, the effects of IRF2BP1 and JDP2 on the ATF2-dependent activation are additive.…”

“…JDP2 has effects on various cellular processes. It mediates the differentiation of myoblasts [5] and osteoclasts [6], inhibits the differentiation of adipocytes [7] and embryonic carcinoma cells [8], acts as a tumor suppressor in NIH3T3 cells and prostate cancer cell lines [9], induces the partial transformation of chick embryonic fibroblasts [10], and functions as a cell-survival protein [11] and as a progesterone receptor coactivator [12]. The mechanisms of JDP2-mediated transcriptional repression may include the regulation of nucleosome assembly and histone acetylation [13].…”

JDP2 suppresses adipocyte differentiation by regulating histone acetylation

“…[14][15][16] JDP2 can function not only as a transcriptional repressor but also as a coactivator in various types of cell, 15,[17][18][19][20] and it is involved in a variety of biological phenomena such as proliferation and differentiation of cells and apoptosis. 14,15,17,18,[20][21][22] For example, forced expression of JDP2 represses the retinoic acid-mediated (RA-mediated) transcription of the c-jun gene and the differentiation of F9 cells in response to RA. 18 By contrast, the expression of an exogenous gene for JDP2 promotes the formation of C2 myotube and strong expression of major myogenic markers in C2 myoblasts.…”