期刊
BIOCHEMICAL JOURNAL
卷 409, 期 -, 页码 389-398出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20070860
关键词
AMP-activated protein kinase (AMPK); growth arrest; HuR; importin alpha 1; intestinal epithelium; ornithine decarboxylase
资金
- Intramural NIH HHS [Z01 AG000393] Funding Source: Medline
- NCCIH NIH HHS [R01 AT004148] Funding Source: Medline
- NIAID NIH HHS [R21 AI068432, AI-68432] Funding Source: Medline
- NIDDK NIH HHS [R01 DK057819, DK-61972, DK-57819, R01 DK061972, R01 DK068491, DK-68491] Funding Source: Medline
Polyamines are required for maintenance of intestinal epithelial integrity, and a decrease in cellular polyamines increases the cytoplasmic levels of RNA-binding protein HuR stabilizing p53 and nucleophosmin mRNAs, thus inhibiting IEC (intestinal epithelial cell) proliferation. The AMPK (AMP-activated protein kinase), an enzyme involved in responding to metabolic stress, was recently found to be implicated in regulating the nuclear import of HuR. Here, we provide evidence showing that polyamines modulate subcellular localization of HuR through AMPK-regulated phosphorylation and acetylation of Imp alpha 1 (importin alpha 1) in IECs. Decreased levels of cellular polyamines as a result of inhibiting ODC (ornithine decarboxylase) with DFMO (D,L-alpha-difluoromethylornithine) repressed AMPK activity and reduced Imp alpha 1 levels, whereas increased levels of polyamines as a result of ODC overexpression induced both AMPK and Imp alpha 1 levels. AMPK activation by overexpression of the AMPK gene increased Imp alpha 1 but reduced the cytoplasmic levels of HuR in control and polyamine-deficient cells. IECs overexpressing wild-type Imp alpha 1 exhibited a decrease in cytoplasmic HuR abundance, while cells overexpressing Imp alpha 1 proteins bearing K22R (lacking acetylation site), S105A (lacking phosphorylation site) or K22R/S105A (lacking both sites) mutations displayed increased levels of cytoplasmic HuR. Ectopic expression of these Imp alpha 1 mutants also prevented the increased levels of cytoplasmic HuR following polyamine depletion. These results indicate that polyamine-mediated AMPK activation triggers HuR nuclear import through phosphorylation and acetylation of Imp alpha 1 in IECs and that polyamine depletion increases cytoplasmic levels of HuR as a result of inactivation of the AMPK-driven Imp alpha 1 pathway.
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