title: Interaction of polyamines and mTOR signaling in the synthesis of antizyme (AZ).
abstract: Tissue polyamine levels are largely determined by the activity of ornithine decarboxylase (ODC, EC 4.1.17), which catalyzes the conversion of ornithine to the diamine putrescine. The activity of the enzyme is primarily regulated by a negative feedback mechanism involving ODC antizyme (AZ). Our previous studies demonstrated that AZ synthesis is stimulated by the absence of amino acids, the levels of which are sensed by the mTOR complex containing TORC1, which is stimulated by amino acids and inhibited by their absence, and TORC2 the function of which is not well defined. Polyamines, which cause a +1 ribosomal frameshift during the translation of AZ mRNA are required to increase AZ synthesis in both the presence and absence of amino acids. Amino acid starvation increases TORC2 activity. We have demonstrated that mTORC2 activity is necessary for AZ synthesis in the absence of amino acids. Tuberous sclerosis protein (TSC), a negative regulator of mTOR function regulates the activities of both the TORC1 and TORC2. TSC2 knockdown increased mTORC1 activity with concomitant inhibition of mTORC2 activity eliminating AZ induction in the absence of amino acids as well as that induced by spermidine. Thus, these results clearly demonstrate that in addition to polyamines, mTORC2 activity is necessary for AZ synthesis. Moreover, our results support a role for mTORC2 in the synthesis of a specific protein, AZ, which regulates growth of intestinal epithelial cells.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA. Electronic address: rray3@uthsc.edu.
authors.forename: Ramesh M
authors.initials: RM
authors.lastname: Ray
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Mitul
authors.initials: M
authors.lastname: Bavaria
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Leonard R
authors.initials: LR
authors.lastname: Johnson
mesh_terms: D000818:Animals; D015317:Biogenic Polyamines / Q000494:pharmacology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008817:Mice, Mutant Strains; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D015317:Biogenic Polyamines; D046912:Multiprotein Complexes; D011506:Proteins; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C031017:ornithine decarboxylase antizyme; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: AKT; Amino acids; Mouse embryonic fibroblasts; Ornithine decarboxylase; Spermidine; TSC2; mTORC1/2; p70S6 kinase