title: Unrestrained mammalian target of rapamycin complexes 1 and 2 increase expression of phosphatase and tensin homolog deleted on chromosome 10 to regulate phosphorylation of Akt kinase.
abstract: Tuberous sclerosis complex 2 (TSC2) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function to block growth factor-induced mammalian target of rapamycin (mTOR) signaling and are mutated in autosomal dominant hamartoma syndromes. mTOR binds to a spectrum of common and different proteins to form TOR complex 1 (TORC1) and TORC2, which regulate cell growth, division, and metabolism. TSC2 deficiency induces constitutive activation of mTOR, leading to a state of insulin resistance due to a negative feedback regulation, resulting in reduced Akt phosphorylation. We have recently described an alternative mechanism showing that in TSC2 deficiency, enhanced PTEN expression contributes to reduced Akt phosphorylation. To explore the mechanism of PTEN regulation, we used rapamycin and constitutively active mTOR to show that TORC1 increases the expression of PTEN mRNA and protein. We found that in TSC2(-/-) mouse embryonic fibroblasts expression of a kinase-dead mutant of mTOR, which inhibits both TORC1 and TORC2, decreases the expression of PTEN via transcriptional mechanism. Furthermore, kinase-dead mTOR increased and decreased phosphorylation of Akt at catalytic loop site Thr-308 and hydrophobic motif site Ser-473, respectively. Moreover, inhibition of deregulated TORC1 in TSC2-null mouse embryonic fibroblasts or in 293 cells by down-regulation of raptor decreased the levels of the transcription factor Hif1α and blocked PTEN expression, resulting in enhanced phosphorylation of Akt at Thr-308 and Ser-473. Finally, knockdown of rictor or mSin1 attenuated the expression of Hif1α, which decreased transcription of PTEN. These results unravel a previously unrecognized cell-autonomous function of TORC1 and TORC2 in the up-regulation of PTEN, which prevents phosphorylation of Akt and may shield against the development of malignancy in TSC patients.
authors.affiliation: Veterans Affairs Research, South Texas Veterans Health Care System, University of Texas Health Science Center, San Antonio, Texas 78229, USA.
authors.forename: Falguni
authors.initials: F
authors.lastname: Das
authors.forename: Nandini
authors.initials: N
authors.lastname: Ghosh-Choudhury
authors.forename: Nirmalya
authors.initials: N
authors.lastname: Dey
authors.forename: Chandi Charan
authors.initials: CC
authors.lastname: Mandal
authors.forename: Lenin
authors.initials: L
authors.lastname: Mahimainathan
authors.forename: Balakuntalam S
authors.initials: BS
authors.lastname: Kasinath
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
authors.forename: Goutam Ghosh
authors.initials: GG
authors.lastname: Choudhury
mesh_terms: D000818:Animals; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C500984:CRTC1 protein, human; C493245:CRTC2 protein, human; C519509:Crtc1 protein, mouse; C504923:Crtc2 protein, mouse; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000624653:TSC2 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse