the pathogenic progress culminating in b-cell dysfunction and failure. Under normoglycemic conditions, acute elevation of extracellular glucose and intracellular cAMP levels stimulate NeuroD expression, whereas the same stimuli are interpreted as repressive signals under hyperglycemic conditions. This divergent response is determined by the tonic level of pCREB and the continuance of ICER expression. In the absence of a deactivation pathway operated by PP2A under chronic hyperglycemia, CREB remains constantly activated, and further stimulation by glucose or forskolin above a physiological threshold prolongs the expression of a negative regulator ICER. Excessive production of ICER proteins in turn leads to repression of the NeuroD promoter. As insulin transcription is negatively regulated by ICER and positively by NeuroD the insulin synthesis/ expression can be influenced directly by ICER and indirectly through ICER-mediated NeuroD silencing. As mentioned above, NeuroD is essential for the normal development, functional maturation of pancreatic b-cells, and maintenance of pancreatic b-cell physiology. NeuroD regulates the expression of other factors critical in glucose sensing and insulin exocytosis. These proteins include glucokinase, a rate-limiting enzyme of glucose metabolism; the islet-specific glucose-6-phosphatase catalytic subunitrelated protein; secretin; Pax6; SUR1, the regulatory subunit of the ATP-sensitive K+ channel; SNAP25; syntaxin1A; piccolo; and Noc2. Therefore, downregulation of NeuroD in chronic hyperglycemia may not only decrease insulin transcription but also attenuate insulin secretion by affecting the glucose sensing and insulin exocytosis machinery. Taken together, ICER-mediated repression of NeuroD synthesis under hyperglycemic conditions may be a critical pathogenic process leading to the impaired insulin depletion, secretion. In experiments performed under high glucose conditions, the CREs of ICER and NeuroD consistently responded to glucose or cAMP signals in the opposite ways such that ICER was upregulated while NeuroD was repressed both in islets and HIT cells. The opposite responses of CREs are possibly attributable to the several facts. First, the CRE of the ICER gene is activated by the active pCREB in the early phase after forskolin stimulus, whereas the CRE of NeuroD is influenced by the ratio of repressors to activators in the late phase. The ICER:CREM ratio is similarly shown to be a key regulator for homeostatic expression of pineal hormones such as melatonin in accordance with circadian rhythm in neuroendocrine cells. Second, diverse flanking sequences around CREs may display differential affinities for ICER, CREB, and CREM. Finally, the contribution of CREB signals to the NeuroD gene may be less than that of ICER, because NeuroD PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/22189542 transcription is cooperatively regulated by several factors, including Ngn3 and CREB, whereas ICER is solely regulated by CREB. Ser/Thr protein phosphatases share substrates but differ in terms of metal ion requirement. 
Specifically, PP2A does not contain metal ions, whereas PP2B/calcineurin requires Ca2+ ions The siRNA was designed to target PP2A Ca that is highly conserved among species including hamster-derived HIT cells. Depletion of PP2A Ca was verified by RT-PCR and western analysis. In HIT cells transfected with PP2A Ca-specific siRNA, pCREB level was persistently enhanced in the presence of 5.5 mM glucose regardless of forskolin Pomalidomide treatment. Concomitantly, ICER was
