Cyclin-Dependent Kinase Inhibitor 1/p21 Initiates Apoptosis in Beta Cells and Rat Islets

Diabetes is characterized by a decline in functional pancreatic beta cell mass resulting in insufficient insulin levels to maintain glucose homeostasis. Beta cell mass is regulated by a dynamic balance of various cellular processes, including cell growth, proliferation, senescence, apoptosis and cell death. Furthermore, the cell cycle machinery is involved in these events and is synchronized by various proteins such as cyclin-dependent kinase inhibitor 1, or p21, a cell cycle inhibitor protein (CIP). Whereas p21 has previously been reported to protect some types of cells from apoptosis, its role in the beta cell is unclear. Interestingly, in a screen of CIP expression, p21 was the only inhibitor upregulated in 832/13 cells (a beta cell line) and rodent islets (the endogenous source of beta cells) by two pharmacologic inducers of cell death, dexamethasone and thapsigargin. We hypothesized that beta cell stress upregulates p21 to activate the apoptotic pathway. To this end, an adenovirus was used to overexpress p21 in pancreatic rat islets and 832/13 cells. [³H]-thymidine incorporation and flow cytometry of p21-overexpressing beta cells indicated a decrease in DNA replication and cell cycle arrest at G2.  Moreover, cleavage of caspase-3 protein and the number of apoptotic cells were 8.42- and 2.16-fold higher, respectively, with p21 overexpression compared to controls. In summary, transcriptional activation of p21 during beta cell stress not only inhibits proliferation and halts cell cycle in the G2 phase but also results in caspase-3 activation and apoptosis. Further investigation is necessary to determine how p21 stimulates beta cell apoptosis.