Schematic diagram depicting the joint roles of the UPR in regulating Mcl-1 expression by proteasome inhibition. In response to bortezomib, e-IF2α is phosphorylated and the ATF4 branch is activated to trigger protective effects for cell survival by up-regulating the expression of the anti-apoptotic protein Mcl-1. Bortezomib shows completely contrary effects, either promoting or inhibiting XBP1 splicing in different MM cell lines, suggesting that XBP1 splicing is not directly involved in bortezomib-induced Mcl-1 expression. Bortezomib can increase the cleavage of ATF6 to form active ATF6α, which also plays a role in regulating Mcl-1.