Elucidation of DECODE cycle that regulates homeostasis mediated by protein modification.

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We have found the ubiquitin-dependent degradation of the forkhead transcription factor・Foxo1 coupled with the phosphorylation mediated via PKB that is activated by insulin-mediated signaling pathway and set out a new mode of insulin action that affects the fate of protein stabilization. We discovered the reduced affinity to the recognition DNA sequence of Foxo1 acetylated by CBP, leading to gene repression of the target genes and demolished the general concept that acetylation of transcription factors induces gene activation. We also demonstrated the re-activation of Foxo1 deacetylated by NAD^+-dependent Sir2. In the present study, we revealed that acetylated Foxo1 is increasingly phosphorylated by PKB and that Foxo1 is methylated by protein arginine methyltransferase・PRMT1 and then the phosphorylation of Foxo1 by PKB is inhibited by the methylation. Furthermore, we illustrated the apoptosis induction mediated by the increased arginine methylation of Foxo1 by PRMT1 in response to H_2O_2 oxidative stress through the Bim gene activation and proposed a novel arginine methylation code as a cross-talk regulation between methylation and phosphorylation.