title: Functional implications of novel human acid sphingomyelinase splice variants.
abstract: BACKGROUND
  Acid sphingomyelinase (ASM) hydrolyses sphingomyelin and generates the lipid messenger ceramide, which mediates a variety of stress-related cellular processes. The pathological effects of dysregulated ASM activity are evident in several human diseases and indicate an important functional role for ASM regulation. We investigated alternative splicing as a possible mechanism for regulating cellular ASM activity.
  
  
  RESULTS
  We identified three novel ASM splice variants in human cells, termed ASM-5, -6 and -7, which lack portions of the catalytic- and/or carboxy-terminal domains in comparison to full-length ASM-1. Differential expression patterns in primary blood cells indicated that ASM splicing might be subject to regulatory processes. The newly identified ASM splice variants were catalytically inactive in biochemical in vitro assays, but they decreased the relative cellular ceramide content in overexpression studies and exerted a dominant-negative effect on ASM activity in physiological cell models.
  
  
  CONCLUSIONS
  These findings indicate that alternative splicing of ASM is of functional significance for the cellular stress response, possibly representing a mechanism for maintaining constant levels of cellular ASM enzyme activity.
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Cosima
authors.initials: C
authors.lastname: Rhein
authors.forename: Philipp
authors.initials: P
authors.lastname: Tripal
authors.forename: Angela
authors.initials: A
authors.lastname: Seebahn
authors.forename: Alice
authors.initials: A
authors.lastname: Konrad
authors.forename: Marcel
authors.initials: M
authors.lastname: Kramer
authors.forename: Christine
authors.initials: C
authors.lastname: Nagel
authors.forename: Jonas
authors.initials: J
authors.lastname: Kemper
authors.forename: Jens
authors.initials: J
authors.lastname: Bode
authors.forename: Christiane
authors.initials: C
authors.lastname: Mühle
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.forename: Martin
authors.initials: M
authors.lastname: Reichel
authors.forename: Cord-Michael
authors.initials: CM
authors.lastname: Becker
authors.forename: Johannes
authors.initials: J
authors.lastname: Kornhuber
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D015153:Blotting, Western; D002518:Ceramides / Q000378:metabolism; D003001:Cloning, Molecular; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D019075:Electrophoresis, Capillary; D040461:Gene Components; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics*
chemical_list: D002518:Ceramides; D017931:DNA Primers; D007527:Isoenzymes; D009841:Oligonucleotides; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase