| Autor: |
Bandyopadhyay S; Department of Cell Biology, Lerner Research Institute and Cleveland Clinic Lerner College of Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA., Harris DP, Adams GN, Lause GE, McHugh A, Tillmaand EG, Money A, Willard B, Fox PL, Dicorleto PE |
| Jazyk: |
angličtina |
| Zdroj: |
Molecular and cellular biology [Mol Cell Biol] 2012 Apr; Vol. 32 (7), pp. 1202-13. Date of Electronic Publication: 2012 Jan 23. |
| DOI: |
10.1128/MCB.05977-11 |
| Abstrakt: |
The induction of proinflammatory proteins in stimulated endothelial cells (EC) requires activation of multiple transcription programs. The homeobox transcription factor HOXA9 has an important regulatory role in cytokine induction of the EC-leukocyte adhesion molecules (ELAM) E-selectin and vascular cell adhesion molecule 1 (VCAM-1). However, the mechanism underlying stimulus-dependent activation of HOXA9 is completely unknown. Here, we elucidate the molecular mechanism of HOXA9 activation by tumor necrosis factor alpha (TNF-α) and show an unexpected requirement for arginine methylation by protein arginine methyltransferase 5 (PRMT5). PRMT5 was identified as a TNF-α-dependent binding partner of HOXA9 by mass spectrometry. Small interfering RNA (siRNA)-mediated depletion of PRMT5 abrogated stimulus-dependent HOXA9 methylation with concomitant loss in E-selectin or VCAM-1 induction. Chromatin immunoprecipitation analysis revealed that PRMT5 is recruited to the E-selectin promoter following transient HOXA9 binding to its cognate recognition sequence. PRMT5 induces symmetric dimethylation of Arg140 on HOXA9, an event essential for E-selectin induction. In summary, PRMT5 is a critical coactivator component in a newly defined, HOXA9-containing transcription complex. Moreover, stimulus-dependent methylation of HOXA9 is essential for ELAM expression during the EC inflammatory response. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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