HUMAN PROGESTERONE AND GLUCOCORTICOID NUCLEAR RECEPTORS ARE CO-REPRESSED BY THE HOMEOBOX PROTEIN DUX4 IN HEK293 CELLS

HARPER, SCOTT; SAAD, NIZAR; QUINTERO, JULIETA; ROSA, ALBERTO L

Salta

Congreso; Reunión Conjunta de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular; 2019

Sociedad Argentina de Investigación Bioquímica y Biología Molecular

DUX4 is a transcription factor that regulates the expression of zygote activated genes in placental mammals. We have demonstrated that DUX4 is a toxic pro-apoptotic protein associated to the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD), the second most common form of inherited myopathy in humans. We also showed that DUX4 co-repress the activity of the progesterone and glucocorticoid nuclear receptor (NR) in T47D and HepG2 (reconstituted system) cellsa,b. Here we explored if DUX4 also co-regulates the activity of the glucocorticoid (GC) and progesterone (PR) nuclear receptors. The activity of DUX4 on these NRs was studied in a reconstituted system on cultured HEK293 cells, which do not express the GC or PR nuclear receptors. Cells were co-transfected with a plasmid expressing either GC or PR nuclear receptors and a reporter system MMTV-Luc/Renilla. The potential co-repressor activity of DUX4 was monitored using a plasmid expressing either wild-type or tagged versions of DUX4. Results of these studies indicate that DUX4 dramatically inhibits in HEK293 cells the transcriptional activity of the GC and PR nuclear receptors. Taken together, our data show that DUX4 is also a strong co-repressor of the GC and PR NRs in the reconstituted system of cultured HEK293 cells. Although DUX4 is mostly considered a transcriptional activator, our results show that this protein could indirectly modulate gene expression by repressing the activity of hormone NRs