title: The role of IMP dehydrogenase 2 in Inauhzin-induced ribosomal stress.
abstract: The 'ribosomal stress (RS)-p53 pathway' is triggered by any stressor or genetic alteration that disrupts ribosomal biogenesis, and mediated by several ribosomal proteins (RPs), such as RPL11 and RPL5, which inhibit MDM2 and activate p53. Inosine monophosphate (IMP) dehydrogenase 2 (IMPDH2) is a rate-limiting enzyme in de novo guanine nucleotide biosynthesis and crucial for maintaining cellular guanine deoxy- and ribonucleotide pools needed for DNA and RNA synthesis. It is highly expressed in many malignancies. We previously showed that inhibition of IMPDH2 leads to p53 activation by causing RS. Surprisingly, our current study reveals that Inauzhin (INZ), a novel non-genotoxic p53 activator by inhibiting SIRT1, can also inhibit cellular IMPDH2 activity, and reduce the levels of cellular GTP and GTP-binding nucleostemin that is essential for rRNA processing. Consequently, INZ induces RS and the RPL11/RPL5-MDM2 interaction, activating p53. These results support the new notion that INZ suppresses cancer cell growth by dually targeting SIRT1 and IMPDH2.
authors.affiliation: Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.
authors.forename: RuiZhi
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States.
authors.forename: Amber
authors.initials: A
authors.lastname: Mosley
authors.affiliation: Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.
authors.forename: Shelya X
authors.initials: SX
authors.lastname: Zeng
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, United States.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xing
authors.affiliation: Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.
authors.forename: Hua
authors.initials: H
authors.lastname: Lu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006150:Guanine Nucleotides / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010640:Phenothiazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C469949:GNL3 protein, human; D006150:Guanine Nucleotides; D007211:Indoles; D009687:Nuclear Proteins; D010640:Phenothiazines; D034741:RNA, Small Interfering; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C573921:inauzhin; C027624:ribosomal protein L11; C549166:ribosomal protein L5, human; D007168:IMP Dehydrogenase; C501687:IMPDH2 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D019204:GTP-Binding Proteins
keywords: IMPDH2; Inauhzin; MDM2; cell biology; human; nucleostemin; p53; ribosomal stress