Endoplasmic reticulum (ER) stress has been implicated as a causative factor in the development of pancreatic beta-cell dysfunction and death resulting in type 2 diabetes. This thesis examined the role of ATF6beta in the ER stress response of beta-cells. Using an ATF6beta-specific antibody, expression of full-length ATF6beta was detected in various insulinoma cell lines and rodent islets and the induction of the active form (ATF6beta-p60) under ER stress conditions. Knock-down of ATF6beta in INS-1 832/13 cells did not affect mRNA induction of known ER stress response genes in response to tunicamycin-induced ER stress, however it increased the susceptibility of beta-cells to apoptosis. Conversely, overexpression of ATF6beta-p60 reduced the apoptotic phenotype. Microarray results suggest ATF6beta functions to induce expression of adaptive genes also regulated by ATF6alpha, but also several specific targets genes. These findings have increased our understanding of the role of ATF6beta in the ER stress response of beta-cells.

Endoplasmic reticulum (ER) stress has been implicated as a causative factor in the development of pancreatic beta-cell dysfunction and death resulting in type 2 diabetes. This thesis examined the role of ATF6beta in the ER stress response of beta-cells. Using an ATF6beta-specific antibody, expression of full-length ATF6beta was detected in various insulinoma cell lines and rodent islets and the induction of the active form (ATF6beta-p60) under ER stress conditions. Knock-down of ATF6beta in INS-1 832/13 cells did not affect mRNA induction of known ER stress response genes in response to tunicamycin-induced ER stress, however it increased the susceptibility of beta-cells to apoptosis. Conversely, overexpression of ATF6beta-p60 reduced the apoptotic phenotype. Microarray results suggest ATF6beta functions to induce expression of adaptive genes also regulated by ATF6alpha, but also several specific targets genes. These findings have increased our understanding of the role of ATF6beta in the ER stress response of beta-cells.