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p300 acetyltransferase activity differentially regulates the localization and activity of the FOXO homologues in skeletal muscle
Author(s) -
Senf Sarah Marie,
Sandesara Pooja B.,
Judge Andrew Robert
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.lb601
Subject(s) - foxo1 , skeletal muscle , c2c12 , transcription factor , foxo3 , acetyltransferase , reporter gene , muscle atrophy , biology , microbiology and biotechnology , chemistry , endocrinology , medicine , gene , gene expression , myogenesis , biochemistry , acetylation
The Forkhead Box O (FOXO) transcription factors are both necessary and sufficient for skeletal muscle atrophy. Therefore understanding the mechanisms of FOXO regulation in skeletal muscle is of significant importance. The objective of the current study was to determine if FOXO signaling is regulated in skeletal muscle via the acetyltransferase (HAT) activities of p300/CBP. Gene transfer of rat soleus muscle with a dominant‐negative (d.n.) p300, which lacks HAT activity and inhibits endogenous p300 HAT activity, increased FOXO reporter activity and induced transcription from the promoter of the atrophy‐related gene, atrogin‐1. Conversely, gene transfer of either WT p300 or WT CBP repressed FOXO activation and atrogin‐1 in response to muscle disuse, and in C2C12 cells in response to acute starvation. Co‐transfection of FOXO1, FOXO3a or FOXO4 with the p300 constructs further identified p300 HAT activity to differentially regulate the activity of the FOXO factors. Decreased HAT activity potently increased FOXO3a transcriptional activity, while increased HAT activity repressed FOXO3a activity and prevented its nuclear localization in response to nutrient deprivation. In contrast, p300 increased FOXO1 nuclear localization. In summary, this study provides the first evidence to support the acetyltransferase activities of p300/CBP in regulating FOXO signaling in skeletal muscle.