This work was supported by NIH NIDDK grants R01 DK068157 and P01 DK049210 (to D.A. Stoffers) and NIH grant T32-GM07229 (to K.C. Claiborn).
Journal of Clinical Investigation
Transcription factors, Homeobox genes -- Stability -- Effect of transcription factors on, Pancreatic beta cells
The homeodomain transcription factor pancreatic duodenal homeobox 1 (Pdx1) is a major mediator of insulin transcription and a key regulator of the β cell phenotype. Heterozygous mutations in PDX1 are associated with the development of diabetes in humans. Understanding how Pdx1 expression levels are controlled is therefore of intense interest in the study and treatment of diabetes. Pdx1 C terminus–interacting factor-1 (Pcif1, also known as SPOP) is a nuclear protein that inhibits Pdx1 transactivation. Here, we show that Pcif1 targets Pdx1 for ubiquitination and proteasomal degradation. Silencing of Pcif1 increased Pdx1 protein levels in cultured mouse β cells, and Pcif1 heterozygosity normalized Pdx1 protein levels in Pdx1+/– mouse islets, thereby increasing expression of key Pdx1 transcriptional targets. Remarkably, Pcif1 heterozygosity improved glucose homeostasis and β cell function and normalized β cell mass in Pdx1+/– mice by modulating β cell survival. These findings indicate that in adult mouse β cells, Pcif1 limits Pdx1 protein accumulation and thus the expression of insulin and other gene targets important in the maintenance of β cell mass and function. They also provide evidence that targeting the turnover of a pancreatic transcription factor in vivo can improve glucose homeostasis.
Claiborn, K. C., Sachdeva, M. M., Cannon, C. E., Groff, D. N., Singer, J. D., and Stoffers, D. A. (2010). Pcif1 modulates Pdxl protein stability and pancreatic beta cell function and survival in mice. Journal of Clinical Investigation, 120(10), 3713-3721