STUDY OF ISOMERASE PROTEINS AS NEW REGULATORS IN THE ACTIVATION OF TRANSCRIPTION FACTORS RELATED TO STRESS AND INFLAMMATION

ERLEJMAN A.G.

Buenos Aires

Congreso; LXII Reunión anual de la Sociedad Argentina de Investigación Clínica (SAIC) en el marco de la Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedad Argenitna de Investigación Clínica

The study of proteins involved in biological re sponse is important in order to promote the discovery of new regulators in signalling pathways. In certain ma lignancies, it is known that some pathways are altered, such as Nuclear Factor Kappa B (NF-kB) and Activator Protein 1 (AP-1) in chronic inflammation. In particular, we study new regulators for the activation of transcription factors related to stress and inflammation such as NF kB and AP-1, with the final goal of provide new molec ular target as a promising approach in therapeutic field. FK506-binding proteins (FKBPs) are Hsp90 Co-chap erones with peptidylprolyl-isomerase enzymatic activi ty, suppressed by the FK506 drug. Previously, FKBP51 and FKBP52 were characterized as steroid receptors modulators. We demonstrated that FKBP51 impairs NF kB (p65/p50) activity, while FKBP52 enhances it. Fur thermore, NF-kB target genes were highly induced by FKBP52, and its isomerase activity was decisive in this regulation. Importantly, both basal phospho-p65 and to tal p65 protein level were increased by FKBP52. In this context NF-kB activity was favored by a higher FKBP52/ FKBP51 ratio. Moreover, in trophoblast cells AP-1 has an important regulatory role. Preeclamptic placentas show alterations on c-fos and FKBP52 expression. Our findings revealed that FKBP52 stimulated AP-1 transcriptional ac tivity and promoted greater c-fos protein level. Interest ingly, the overexpressed FKBP52 produced higher level of pERK/ERK for longer time. We propose FKBP52 as new key regulator on AP-1 and NF-B signalling, empha sizing its isomerase activity as essential. Thus, we sug gest FKBP52 isomerase activity as an interesting target to prevent AP-1 and NF-kB biological activity.This find ings represent a novel contribution in the development of new therapeutic agents for inflammatory diseases. Financial support: UBA, CONICET and PICT 2015-1603