ERK and AKT inhibitors enhance ATO induced apoptosis in non APL AML cells by 1)

Recent mobile based studies have implicated the activation of mTOR complex 1 downstream of Akt in the induction of SREBP isoforms. The primary mechanism by which Akt Everolimus activates mTORC1 is through the phosphorylation and inhibition of the TSC2 protein within the complex. This protein complex acts as a GTPase activating protein to get a Ras related small G protein called Rheb, thereby improving its transformation to the GDP bound off state. GTP bound Rheb stimulates mTORC1 kinase activity and downstream signaling. Thus, Akt mediated inhibition of the TSC1?TSC2 complex serves to trigger Rheb and mTORC1. Significantly, increased activation of mTORC1, through the expression of an allele of Akt or genetic disturbance of the TSC1 TSC2 complex, is found to activate SREBP isoforms and promote an SREBP dependent increase in de novo lipid synthesis. Furthermore, a current study shows that the ability of insulin to stimulate SREBP1c in rat hepatocytes is sensitive for the mTORC1 specific inhibitor rapamycin. SREBP1c regulation is fairly complex. The protein is synthesized as an inactive precursor that lives in complex with SREBP cleavage activating protein in the endoplasmic Plastid reticulum membrane, where it's sequestered through the interaction of SCAP with INSIG proteins. Through a poorly comprehended process, insulin stimulates trafficking of the SREBP1c SCAP complex to the Golgi, where SREBP1c is proteolytically processed to generate the active transcription factor. The active form of SREBP1c is sensitive to proteasomal degradation but can enter the nucleus to have interaction its transcriptional goals, including its own gene promoter and these encoding the major enzymes of fatty acid synthesis. A collection of past studies has implicated Akt and insulin in controlling different facets of SREBP1c activation. While the systems remain to be determined, mTORC1 signaling downstream of Akt appears to control some part of the Cathepsin Inhibitor 1 trafficking or control of SREBP isoforms, without apparent effects on translation or stability. The role of mTORC1 activation within the metabolic reaction of the liver to insulin and nutrients is defectively understood. Elevated levels of mTORC1 signaling have been connected with conditions of hepatic insulin resistance. In vitro, cell intrinsic insulin resistance can be caused by mTORC1 signaling through negative feedback mechanisms affecting upstream regulators of Akt. To get an in vivo role for these feedback mechanisms controlling insulin sensitivity, knockout of S6K1, a downstream target triggered by mTORC1, results in an elevated response of Akt signaling to insulin in the mouse liver, along with other metabolic tissues. But, the phenotype of the S6K1 knockout mouse is confounded with a pronounced decrease in adiposity. Consequently, liver specific genetic models are needed to better determine the hepatocyte implicit functions of mTORC1 in controlling insulin signaling and lipogenesis.