Pancreatic Beta Cell Death: Novel Potential Mechanisms in Diabetes Therapy

Figure 3

Unfolded protein response. (a) Homeostasis: activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1), and PKR-like ER kinase (PERK) mediate the correct functioning of the ER. These regulate pathways that allow for the decongestion and renormalization of the ER activity. (b) Apoptosis intrinsic pathway: chronic stress of the ER activates IRE1, PERK, and ATF6, which then will activate CCAAT enhancer-binding protein homologous protein (CHOP) transcription. This promotes DNA fragmentation and stops the cell cycle and another proapoptotic pathway (see text). ATF6: activating transcription factor 6; IRE1: inositol-requiring enzyme 1; eIF2α: eukaryotic initiation factor 2; mRNA: messenger ribonucleic acid; XBP-1: X-box binding protein 1; ERAD: endoplasmic reticulum-associated protein degradation; CHOP: CCAAT enhancer-binding protein homologous protein; Bcl2: B-cell lymphoma 2; BAX: Bcl-2-like protein 4; CytC: cytochrome c. TRAF2: TNF receptor-associated factor 2; ASK1: apoptosis signal-regulating kinase 1; JNK: c-Jun N-terminal kinase; ATF4: activating transcription factor 4.