Mechanisms involved in tissue-specific apopotosis regulated by glucocorticoids

PECCI, A.

Atenas, Grecia

Simposio; 12 th, International Congress on Hormonal Steroids and Hormones and Cancer; 2006

Hormonal Steroids Society

Glucocorticoids control apoptosis in a tissue-specific manner. In immune cells such as T lymphocytes, they induce apoptosis whereas in epithelial cells of mammary gland and endometrium they protect against apoptotic signals. It was suggested that the opposite control of apoptosis by glucocorticoids is exerted by modulation of a few genes, such as bcl-2, bcl-X, bax and NFƒÛB, in a cell type-specific manner. Multiple effects could be achieved by composite regulatory cross-talks between GR and a variety of nuclear modulators, which are selectively involved in the hormone-dependent expression of specific genes. One of the key genes mediating apoptosis is bcl-X, a member of bcl-2 family. Six different Bcl-X isoforms can be generated by alternative splicing. Some of them exert opposite effects on apoptosis i.e. Bcl-XL protects cells against death, while Bcl-XS antagonizes cell death inhibition. In mammary and endometrial epithelial cells, glucocorticoids induce bcl-X expression and increase the ratio bcl-XL/bcl-XS, leading to an inhibition of apoptosis. In thymocytes glucocorticoids increase apoptosis by inhibiting bcl-X expression and decreasing the ratio bcl-XL/bcl-XS. The 5¡¦-upstream region of the mouse bcl-X gene contains five different promoters, which exhibit a tissue-specific pattern of promoter usage. We described two HREs located immediately upstream of the distal promoter P4, which bind GR in the mammary epithelial HC11 cell line upon hormone addition. This effect correlates with an increased bcl-XL mRNA, suggesting that the antiapoptotic effect of glucocorticoids in this cell type involves a direct induction of bcl-XL through the activation of P4. On thymocytes and on T lymphocyte S49 cell line, the levels of transcripts generated from P4 decrease in response to hormone. ChIP assays show a transient loading of GR to the HREs accompanied by a stable recruitment of STAT5B at a binding site located between the HREs and the P4 TATA box. Inhibition of STAT5 activity reverted glucocorticoid repression to activation of transcription and was accompanied by stable recruitment of GR and RNA Polymerase II to P4. These results suggest that glucocorticoids repress bcl-X expression in thymocytes through a crosstalk with STAT5B contributing to the understanding of the molecular basis for tissue-specific hormone dependent apoptosis.