Regulator of Calcineurin 1 Controls Growth Plasticity of Adult Pancreas

Abstract

Background & Aims-Growth of exocrine pancreas is regulated by GI hormones, notably cholecystokinin (CCK). CCK-driven pancreatic growth requires calcineurin (CN), which activates NFATs (Nuclear Factor of Activated T-cells), but the genetic underpinnings and feedback mechanisms that regulate this response are not known.

Regulation of Normal and Adaptive Pancreatic Growth

“…The 38 genes included feedback inhibitors (Rcan1, Socs3, Rgs2, Socs 2, Lif), growth factors (FGF21, HBEGF) and transcriptional regulators. About 60% had predicted NFAT regulation and CHIP analysis confirmed this for 5 genes in pancreatic 266-6 acinar cells stimulated with calcium ionophore (48). …”

“…RNA microarray analysis of pancreatic genes revealed 38 genes induced by TI two hours after feeding that were at least 70% inhibited by FK-506 (48). These changes were not observed in CCK deficient mice.…”

Rcan1

“…Despite their differences in size, the two are almost equally potent inhibitors of CN (29). Rcan1.4, however, contains tandem NFAT binding sites in its promoter and as shown both in our work (14) and multiple other studies (38,40), its product is the only one among Rcan1 variants whose expression is regulated by CN-NFAT signaling. The alternative Rcan1.1 variant also inhibits calcineurin but is regulated by Notch/Hes1 and oxidative stress (25,33).…”

“…In our past work, we had shown that Rcan1 is the only member of the RCAN family to be induced in response to CCK in the course of pancreatic growth (14). We also detailed its role as a feedback inhibitor of CN-NFAT signaling and established the CN-NFAT-Rcan1 axis as the first molecular switch or negative feedback regulator of adaptive, hormonally-regulated pancreatic growth (14).…”

“…In our past work, we had shown that Rcan1 is the only member of the RCAN family to be induced in response to CCK in the course of pancreatic growth (14). We also detailed its role as a feedback inhibitor of CN-NFAT signaling and established the CN-NFAT-Rcan1 axis as the first molecular switch or negative feedback regulator of adaptive, hormonally-regulated pancreatic growth (14). Briefly, we showed that: (a) Rcan1 overexpression blocks CN-mediated nuclear translocation of NFAT in isolated acini; (b) Rcan1 overexpression both in isolated acini and in vivo blocks CN-mediated transcriptional activation of NFAT, as examined by NFAT-luciferase reporters; and (c) Rcan1 overexpression blocks NFATinduced pro-proliferative gene expression driven by CCK.…”