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p150/Glued Modifies Nuclear Estrogen Receptor Function

Departments of Neurology (S.J.L., C.C., M.M.W.) and Molecular and Integrative Physiology (M.M.W.), University of Michigan, Ann Arbor, Michigan 48109-5622

Address all correspondence and requests for reprints to: Michael Wang, 7629 Med Sci II Box 5622, 1137 Catherine Street, Ann Arbor, Michigan 48109-5622. E-mail: micwang{at}umich.edu.

Estrogen modulates gene expression through interactions with estrogen receptors (ERs) that bind chromosomal target genes. Recent studies have suggested an interaction between the cytoskeletal system and estrogen signaling; these have implicated a role of cytoplasmic microtubules in scaffolding ER and enhancing nongenomic function; in addition, other experiments demonstrate that dynein light chain 1 may chaperone ER to the nucleus, indirectly increasing transcriptional potency. Actin/myosin and dynein light chain 1 are also required for estrogen-mediated chromosomal movement that is required for transcriptional up-regulation of ER targets. We present evidence that the dynactin component, p150/glued, directly influences the potency of nuclear ER function. Increasing the stoichiometric ratio of p150/glued and ER by overexpression enhances estrogen responses. ER enhancement by p150/glued does not appear to be influenced by shifts in subcellular localization because microtubule disruption fails to increase nuclear ER. Rather, we find that modest amounts of p150/glued reside in the nucleus of cells, suggesting that it plays a direct role in nuclear transcription. Notably, p150/glued is recruited to the pS2 promoter in the presence of hormone, and, in MCF-7 cells, knockdown of p150/glued levels reduces estrogen-dependent transcription. Our results suggest that p150/glued modulates estrogen sensitivity in cells through nuclear mechanisms.