| dc.description.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. | ca_ES |
