Dynamics of BCL-2 family of proteins in early pancreatic progenitors and β-cells

• Main Author: Loo, Larry Sai Weng
• Other Authors: Francesc Xavier Roca Castella
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2020
• Subjects: Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/142359
• Institution: Nanyang Technological University

BCL-2 family proteins play an important role in the regulation of cell survival and death. However, there are also certain members that exhibit tissue- and developmental stage-specific expression and function. Here, I report a unique reciprocal relationship between BCL-xL (not BCL2) and BAK during early human pancreatic differentiation. The association of BCL-xL but not BCL2 with BAK has also been reported to keep apoptosis in check, albeit not specifically during pancreatic development. This is consistent with our findings that the compensatory increase in BCL2 protein expression upon BCL-xL inhibition with WEHI-539 is insufficient to curb the BAK mediated increase in cleaved caspase 3 and the triggering of the caspase cascade. I also found that the downregulation of BCL2L1/BCL-xL expression and function resulted in a decrease in early pancreatic gene and protein expression. However, BCL-xL is known to be dispensable during rodent beta cell development but rather is important for protection against apoptotic stimuli in mature beta cells (Carrington et al., 2009). Therefore, I propose that BCL-xL might be indirectly involved in human pancreatic specification that is ultimately crucial for proper beta cell function.