Molecular and Cellular Mechanism of Androgen Receptor Aggresomes on Er Stress-Mediated Apoptosis during Embryonic Stem Cell Differentiation

Embryonic stem (ES) cells are capable of being differentiated into various lineages of cells associated with apoptosis. However, the cause and the mechanism of initiation of ES cell apoptosis during differentiation remain largely unknown. It is considered that, differentiation stimuli are needed to begin induction of apoptosis. Therefore, signaling pathways regulating the apoptosis of ES cells during differentiation are of the great interest for further investigation. Base on our preliminary findings that the increasing expression of AR aggresomes is associated with inducing endoplasmic reticulum (ER) stress chaperones and apoptosis during ES cell differentiation, we hypothesize that accumulation of AR aggresomes may serve as master initiators for the ER stress signal activation to induce naturally occurring apoptosis during early embryogenesis and ER stress chaperones, GRP78 and GRP94, may be required for AR aggresome refolding and suppress AR-mediated apoptosis during ES cell differentiation. In this proposal, we aim to further explore (2) the molecular mechanism of AR aggresomes induced ER stress-signaling cascades, which stimulate the apoptosis of mouse ES cells during differentiation; (1) the influence of ER stress chaperones, GRP78 and GRP94, on AR aggresome refolding and apoptosis during ES cell differentiation, and (3) the physiological and functional significance of AR, signal molecules of ER stress cascades, GRP78 and GRP94 on naturally occurring apoptosis during development. These approaches will allow us to identify the signaling molecules of proximal sensors and downstream ER stress-mediated apoptotic pathways essential for AR-mediated ER stress. In addition, we will be able to conclude whether grp78 and grp94 are interacted with AR aggreasomes to increase the refolding of AR aggresome proteins and suppress AR-mediated ES cell apoptosis during ES cell differentiation. Dissecting these pathways should be valuable in understanding the ES cell physiology of naturally occurring apoptosis during differentiation, allowing us to control the stem cell apoptosis and commitment to a specific cell lineage and ultimately designing cell therapy for diseases that feature misfolded proteins.

Project ID:PC9709-0449
External Project ID:NSC97-2321-B182-004-MY3