Alternative promoter usage and splicing: Regulation of the expresión of Bcl-XL isoform through the activation of the distal promoter P4

ROCHA VIEGAS, LUCIANA; VICENT, G.P.; BEATO, M; PECCI, A.

Baeza

Workshop; 21. Workshop: Coupling between transcription and RNA processing; 2004

Universidad de Andalucía

Bcl-X is one of the members of Bcl-2 family proteins and plays a critical role in the control of apoptosis. At least five different isoforms, produced by alternative splicing, have been described. Some of these isoforms exert opposite effects on programmed cell death. Previously, we have demonstrated that glucocorticoids induce bcl-X expression, and increase the ratio between bcl-XL (antiapopototic) and bcl-XS (apopototic) in mammary and endometrial epithelial cells. However in thymocytes, glucocorticoids inhibit bcl-X expression, and decrease the ratio between bcl-XL and bcl-XS favoring an increase of programmed cell death. The 5?-UTR region of the mouse bcl-X gene contains five different promoters, that exhibit a tissue-specific pattern of promoter usage. Recently, we have demonstrated that the region located immediately upstream of Promoter 4 (P4) contains two hormone response element (HRE)-like sequences which confer in vivo hormone responsiveness to a core promoter and bind glucocorticoid receptor. In epithelial mammary cells, only this promoter is activated upon hormone treatment and this effect correlates with an increase bcl-XL mRNA. On the contrary, on mouse thymocytes the decrease in the level of bcl-XL isoform correlates with an inhibition of P4 activity upon hormonal treatment. Taken together, the results show that on P4 activation GR, the SRC-1 coactivator and the RNA pol II are recruited to the promoter, while on P4 inhibition hormone treatment induces the recruitment of STAT 5 B and the SMRT corepressor complex.