The anti-inflammatory prostaglandin 15-deoxy-delta(12,14)-PGJ2 inhibits CRM1-dependent nuclear protein export.
The signaling molecule 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) has been described as the "anti-inflammatory prostaglandin." Here we show that substrates of the nuclear export receptor CRM1 accumulate in the nucleus in the presence of 15d-PGJ(2), identifying this prostaglandin as a regulator of CRM1-dependent nuclear protein export that can be produced endogenously. Like leptomycin B (LMB), an established fungal CRM1-inhibitor, 15d-PGJ(2) reacts with a conserved cysteine residue in the CRM1 sequence. This covalent modification prevents the formation of nuclear export complexes. Cells that are transfected with mutant CRM1 (C528S) are resistant to the inhibitory effects of LMB and 15d-PGJ(2), demonstrating that the same single amino acid is targeted by the two compounds. Inhibition of the CRM1 pathway by endogenously produced prostaglandin and/or exogenously applied 15d-PGJ(2) may contribute to its anti-inflammatory, anti-proliferative, and anti-viral effects.
Hilliard
Mark
M
UCD Conway Institute, Belfield, Dublin 4, Ireland.
Frohnert
Cornelia
C
Spillner
Christiane
C
Marcone
Simone
S
Nath
Annegret
A
Lampe
Tina
T
Fitzgerald
Desmond J
DJ
Kehlenbach
Ralph H
RH
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000595:Amino Acid Sequence; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D000097606:Exportin 1 Protein
D000893:Anti-Inflammatory Agents; D003545:Cysteine; D005231:Fatty Acids, Unsaturated; D028884:Karyopherins; D050505:Mutant Proteins; D010455:Peptides; D015230:Prostaglandin D2; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C037112:9-deoxy-delta-9-prostaglandin D2; C038753:leptomycin B
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