IRNASUS   26003
INSTITUTO DE INVESTIGACIONES EN RECURSOS NATURALES Y SUSTENTABILIDAD JOSE SANCHEZ LABRADOR S.J.
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
ROLE OF NR BOXES 1 AND 2 ON THE CO-REPRESSOR ACTIVITY OF DUX4 ON THE HUMAN PROGESTERONE NUCLEAR RECEPTOR
Autor/es:
QUINTERO, JULIETA; ROSA, ALBERTO L; PAGNONI, SABRINA; SAAD, NIZAR
Reunión:
Congreso; FSHD International Research Congress; 2020
Institución organizadora:
FSHD Society
Resumen:
Miss-expression of DUX4 in muscle cells is associated to the pathogenesis of FSHD. Previous results from our laboratory demonstrate that DUX4 is a strong co-repressor of the progesterone (PG) nuclear receptor (NR). In this work we analyze the contribution of two NR box motifs (NR1 and NR2), in silico recognized in DUX4 and ubiquitously present in co-regulators of hormone NRs, on the NR corepressor activity of DUX4. A PG responsive reconstituted experimental system, based on cultured HEK293 cells, was developed for these studies. As it was previously observed in T47D and HepG2 cells, the activity of the PG NR was strongly repressed by DUX4 in HEK293 cells. DUX4 mutants DUX4-ΔNR1 and DUX4-ΔNR2, as well as DUX4-NR1s and DUX4-NR2s, carrying either deletions (Δ) or amino acid substitutions (s) at NR box 1 (LDELL374-378) and/or NR box 2 (LLEEL420-424) were also studied in HEK293 cells. The mutants were independently co-transfected into HEK293 cells together with plasmids expressing the PG NR plus a standard luciferase-reporter system (MMTV-Luc/Renilla). A marked decrease in the co-repressor activity of DUX4, on the PR NR, was observed with mutants DUX4-ΔNR2 and DUX4-NR2s. In additional studies we observed that DUX4c, which conserves NR1 and lacks NR2, does not co-repress the PG NR. We concluded that NR box 2 is required for the strong co-repressor activity of DUX4 on the PG NR in HEK293 cells.