Prolactin in the Nucleus

Abstract

Prolactin is a growth factor and hormone involved in stimulating milk production. Prolactin binds to a cytokine type I receptor to initiate a signaling cascade that includes the activation of the transcription factor STAT5. Ligand-occupied prolactin receptor is also internalized, and a small fraction of the internalized prolactin can be found in the nucleus. Rycyzyn and Clevenger investigated the interaction between prolactin and cyclophilin b, a peptidyl-prolyl isomerase known for its role in the endoplasmic reticulum as a protein-folding chaperone and also known to potentiate the prolactin to stimulate proliferation. In transfected cells, the ability of cyclophilin B to potentiate prolactin-stimulated proliferation or transcription was blocked if cyclophilin B was rendered catalytically inactive by mutation. STAT5 was coprecipitated from the nucleus in cells expressing catalytically active cyclophilin B after stimulation of cells with epitope-tagged prolactin (the complex was precipitated with an antibody against the tagged prolactin). The presence of cyclophilin B inhibited the prolactin-stimulated interaction between STAT5 and an inhibitor of STAT5 called PIAS3. Thus, cyclophilin B may promote the entry of prolactin into the nucleus and then, through a mechanism that requires the catalytic activity of cyclophin B, promote the dissociation of a prolactin-stimulated STAT5-PIAS3 interaction, enhancing DNA binding and transcriptional activation. M. A. Rycyzyn, C. V. Clevenger, The intranuclear prolactin/cyclophilin B complex as a transcriptional inducer. Proc. Natl. Acad. Sci. U.S.A. 99 , 6790-6795 (2002). [Abstract] [Full Text]