IKBα and Cancer

Abstract

It has been previously described that although phosphorylation of S32,36 is the instructive mark that targets IKBα for K21,22 ubiquitination and its subsequent degradation by the proteasome, K21,22 sumoylation protects phosphorylated IKBα from degradation thus generating a new unexpected functional Phospho-Sumoilated-IKBα (PS-IKBα)species. We propose that nuclear PS-IKBα negatively regulates transcription of developmental-related genes in collaboration with Polycomb proteins and nuclear co-repressors, and that PS-IkBα is regulating the expression of cancer-related genes. Since gene expression patterns differ between normal and cancer cells, we expect to see differences in IKBα activity between normal and tumor cells. The main objectives for this project are to study the subcellular distribution of PS-IKBα to assess whether there are differences among tumoral and non-tumoral cells, and whether the distribution of PS-IKBa can be modulated by activating or repressing signaling molecules affected in different tumor cell models. In addition, we have generated recombinant IKBα variants to check the association to different protein complexes in the nucleus of different cells paying special attention to tumor/normal pairs. Our experiments demonstrate that S32,36 phosphorylated and posttranslationally modified by SUMO2 at K21,22 IKBα is mainly found bound to chromatin in non-cancer cells, and present in the soluble fractions (non-chromatin bound) in cancer cells. In cancer cells the recruitment of IΚΚs to specific gene promoter causes the liberation of SMRT repressor from the chromatin, and therefore the activation of specific genes. Inhibition of the IKK activity with BAY11-7082 abrogated the accumulation of cytoplasmic PS-IkBα and prompted its translocation to non-soluble nuclear fraction, demonstrating that IKK activity inhibition is sufficient to shuttle IkBα and SUZ12 from the cytoplasm to chromatin fractions. We expect that this shuttling results in the proper regulation of target genes inhibiting the growth of tumoral cells in vitro and in vivo. All these hints together take us closer to reveal the role of chromatin-associated IKBα as a putative tumor suppressor and to the design of new specific anti-cancer therapies.