title: Indoprofen upregulates the survival motor neuron protein through a cyclooxygenase-independent mechanism.
abstract: Most patients with the pediatric neurodegenerative disease spinal muscular atrophy have a homozygous deletion of the survival motor neuron 1 (SMN1) gene, but retain one or more copies of the closely related SMN2 gene. The SMN2 gene encodes the same protein (SMN) but produces it at a low efficiency compared with the SMN1 gene. We performed a high-throughput screen of approximately 47,000 compounds to identify those that increase production of an SMN2-luciferase reporter protein, but not an SMN1-luciferase reporter protein. Indoprofen, a nonsteroidal anti-inflammatory drug (NSAID) and cyclooxygenase (COX) inhibitor, selectively increased SMN2-luciferase reporter protein and endogenous SMN protein and caused a 5-fold increase in the number of nuclear gems in fibroblasts from SMA patients. No other NSAIDs or COX inhibitors tested exhibited this activity.
authors.affiliation: Department of Biological Sciences, Columbia University, Fairchild Center, MC 2406, 1212 Amsterdam Avenue, New York, NY 10027, USA.
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: Lunn
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Allison M
authors.initials: AM
authors.lastname: Martino
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Flaherty
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kelley
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Coovert
authors.forename: Arthur H
authors.initials: AH
authors.lastname: Burghes
authors.forename: Nguyen Thi
authors.initials: NT
authors.lastname: Man
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Morris
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhou
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Androphy
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Sumner
authors.forename: Brent R
authors.initials: BR
authors.lastname: Stockwell
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007216:Indoprofen / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D015854:Up-Regulation
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D017362:Cyclic AMP Response Element-Binding Protein; D016861:Cyclooxygenase Inhibitors; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D007216:Indoprofen; D011451:Prostaglandin-Endoperoxide Synthases