Kennedy's disease. Phosphorylation of the polyglutamine-expanded form of androgen receptor regulates its cleavage by caspase-3 and enhances cell death.
X-linked spinal and bulbar muscular atrophy is a degenerative disease affecting motor neurons that is caused by polyglutamine (polyQ) expansion within the androgen receptor (AR). The polyQ-expanded form of AR is cytotoxic to cells, and proteolytic cleavage enhances cell death. The intracellular signaling pathways activated and/or required for cell death induced by the expanded form of AR (AR112) are unknown. We found that AR regulates mitogen-activated protein kinase (MAP kinase) pathways and, therefore, hypothesized that these pathway(s) may be required for AR112-induced cell death. The polyQ expansion in AR activates three MAP kinase pathways, causing increasing levels of phosphorylation of p44/42, p38, and SAPK/JNK MAP kinase. Inhibitors of either the JNK or p38 pathways had no effect on AR112-induced cell death, suggesting they are not required for polyQ-induced cell death. Strikingly, the MEK1/2 inhibitor, U0126, which selectively inhibits the p44/42 MAP kinase pathway, reduces AR112-stimulated cell death. The inhibition of the MEK1/2 pathway correlates directly with a change in phosphorylation state of the androgen receptor. Mutation of the MAP kinase consensus phosphorylation site in AR at serine 514 blocked AR-induced cell death and the generation of caspase-3-derived cleavage products. We propose a mechanism by which phosphorylation at serine 514 of AR enhances the ability of caspase-3 to cleave AR and generate cytotoxic polyQ fragments.
LaFevre-Bernt
Michelle A
MA
Buck Institute for Aging Research, Novato, California 94945, USA.
Ellerby
Lisa M
LM
D000409:Alanine; D019943:Amino Acid Substitution; D001483:Base Sequence; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D017931:DNA Primers; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000378:metabolism*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012694:Serine; D014162:Transfection; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
D017931:DNA Primers; D004791:Enzyme Inhibitors; D010455:Peptides; D011944:Receptors, Androgen; D011994:Recombinant Proteins; C097188:polyglutamine; D012694:Serine; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000409:Alanine