Estrogen Regulation of Prothymosin Alpha

Abstract

Abstract : Prothymosin a (PTa) is a small highly acidic protein found in the nuclei of virtually all mammalian tissues. Its high conservation in mammals and wide tissue distribution suggest an essential biological role. While the exact mechanism of action of PTa remains elusive, the one constant has been its relationship with the proliferative state of the cell and its requirement for cellular growth and survival. Recently PTa was found to promote transcriptional activity by sequestering the anticoactivator, REA from the Estrogen Receptor (ER) complex. We now report that Estradiol (E2) upregulates PTa mRNA and protein expression. Further studies indicate that ERa regulates PTa gene transcriptional activity. We have also delimited the region of PTa gene promoter involved in ERa mediated transcriptional regulation and identified a novel ERa-binding element. Increased intracellular PTa expression in the presence of estrogen is accompanied by increased nuclear/decreased cytoplasmic localization. Increased nuclear expression of PTa in correlated with increased proliferation as measured by expression. of Ki67 nuclear antigen. Conversely, inhibition of nuclear PTa expression in breast cancer cells using antisense methodology resulted in the inhibition of E2-induced breast cancer cell proliferation. Overall these studies underscore the importance of PTa in estrogen-induced breast cell proliferation.