Browsing by Subject "Mammalian target of rapamycin"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy
    (American Society for Biochemistry and Molecular Biology, 2018-04) Justice, Matthew J.; Bronova, Irina; Schweitzer, Kelly S.; Poirier, Christophe; Blum, Janice S.; Berdyshev, Evgeny V.; Petrache, Irina; Biochemistry and Molecular Biology, School of Medicine
    Activation of the lysosomal ceramide-producing enzyme, acid sphingomyelinase (ASM), by various stresses is centrally involved in cell death and has been implicated in autophagy. We set out to investigate the role of the baseline ASM activity in maintaining physiological functions of lysosomes, focusing on the lysosomal nutrient-sensing complex (LYNUS), a lysosomal membrane-anchored multiprotein complex that includes mammalian target of rapamycin (mTOR) and transcription factor EB (TFEB). ASM inhibition with imipramine or sphingomyelin phosphodiesterase 1 (SMPD1) siRNA in human lung cells, or by transgenic Smpd1+/- haploinsufficiency of mouse lungs, markedly reduced mTOR- and P70-S6 kinase (Thr 389)-phosphorylation and modified TFEB in a pattern consistent with its activation. Inhibition of baseline ASM activity significantly increased autophagy with preserved degradative potential. Pulse labeling of sphingolipid metabolites revealed that ASM inhibition markedly decreased sphingosine (Sph) and Sph-1-phosphate (S1P) levels at the level of ceramide hydrolysis. These findings suggest that ASM functions to maintain physiological mTOR signaling and inhibit autophagy and implicate Sph and/or S1P in the control of lysosomal function.
  • Thumbnail Image
    Item
    Primary cutaneous peripheral T-cell lymphoma, not otherwise specified with mammalian target of rapamycin mutation: A novel finding for targeted treatment
    (Elsevier, 2020-12) De la Sancha, Carlo; Burgin, Callie; Warren, Simon; Hoffmann, Kristin; Davé, Utpal; Nassiri, Mehdi; Pathology and Laboratory Medicine, School of Medicine
    Primary cutaneous peripheral T-cell lymphoma, not otherwise specified (pcPTCL-NOS) is a rare, progressive, and often fatal disease with no specific treatment regimen that presents as rapidly enlarging plaques or nodules. Here, we present a case of progressive pcPTCL-NOS with mammalian target of rapamycin (mTOR) mutation and variable T-cell antigen expression. mTOR mutation in pcPTCL-NOS may represent a new therapeutic target.