Positive and negative regulator Junb : impact on chromatin remodeling and stress response

Abstract

The AP-1 transcription factor is a central player in a multitude of biological processes from normal development to neoplastic transformation causing cancer. Junb, a subunit of AP-1, is special by the fact that it has at the same time activator and repressor functions. While positively regulated Junb target genes are principally required for proper vascular development, negative regulation of cytokines is of crucial importance to suppress pro-inflammatory and tumorigenic phenotypes. In this work, I approached this double-edge role of Junb by addressing two scientific questions: the mode of operation of Junb as negative transcription regulator and its impact in the ER stress response and apoptosis. First, I could show that, in addition to the general view of being an inhibitor of AP-1 by absorbing Jun activity, Junb also represses genes by epigenetic mechanisms. Although Junb did regulate neither the levels of histone acetylation nor the expression of HDACs, DNMTs and co-repressor complexes, few genes showed differential induction by HDAC inhibitors in wild-type and Junb-deficient fibroblasts. Presumably, these genes may be regulated through a yet to be identified Junb-dependent mechanism involving HDACs. Moreover, Junb regulated the DNA methylation of the imprinting control region of the gene H19. The molecular mechanisms involved in Junb-dependent epigenetic regulation appear to be novel and very unusual for an AP-1 member and remains to be fully solved. Secondly, I investigated the role of Junb in ER stress, a condition that has been described to contribute to hypoxia tolerance and tumor progression. Although Junb deficiency resulted in minor changes in the ER stress-triggered unfolded protein response (UPR), Junb-ablated MEFs were resistant towards apoptosis. Very high levels of activated pro-survival kinases resulted in aberrant post-translational modification of BH3-only proteins Bim and Bad and subsequent failure in mitochondria permeabilization and caspases activation. A soluble factor, most likely Pdgfb, elicited a pro-survival autocrine loop causative for the apoptosis resistance in absence of Junb. In summary, the negative regulation of cytokines and growth factors by Junb accounts for most of the deleterious effects observed in absence of Junb, except for the angiogenesis phenotype. Thus, the understanding of how Junb represses genes and the targeting of this specific mechanism would represent a promising therapeutic approach to treat in the future inflammatory disease and cancer.