Bip is a molecular link between the phase I and phase II estrogenic responses in uterus

Uterine estrogenic actions are biphasic, early (phase I) and late (phase II) responses. However, the molecular linkage between these phases is not known. Although certain phase I responses are considered estrogen receptor (ER)alpha and ERbeta independent, the phase II responses are ERalpha dependent. We previously observed that among several genes Bip is induced by estrogen in the mouse uterus in an ER-independent manner as a phase I response. Bip is a member of the chaperone family and plays roles in protein processing and confers cellular protection. However, its role in estrogen-dependent uterine biology is unknown. We show here a new function of Bip in regulating estrogen signaling in the uterus. Bip, induced during the phase I responses, molecularly interacts with ERalpha required for estrogen-mediated phase II growth responses. Utilizing in vivo and in vitro model systems, we found that adenovirus-driven suppression of Bip antagonizes ERalpha-mediated uterine gene transcription. Importantly, down-regulation of Bip compromises estrogen-dependent phase II growth responses with sustained phase I responses. In conclusion, Bip is critical for coordinating estrogen-elicited biphasic responses and serves as a molecular link between ERalpha-independent and -dependent estrogenic responses in the uterus.