Regulation of SRF/CArG-dependent gene transcription during chronic partial obstruction of murine small intestine.
Regulation of SRF/CArG-dependent gene transcription during chronic partial obstruction of murine small intestine.
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DOI：
10.1111/j.1365-2982.2008.01149.x
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发表时间：
2008-07
影响因子：
3.5
通讯作者：
Perrino BA
中科院分区：
文献类型：
--
作者：
Chen J;Chen H;Sanders KM;Perrino BA
肠梗阻会导致各种运动障碍。小肠平滑肌在梗阻时会发生显著的表型变化，但其潜在的分子机制尚不清楚。利用RT-PCR、CHIP、Re-ChIP和Western blotts等方法，我们检测了机械性肠梗阻对血管平滑肌基因表达的影响。梗阻导致一过性增生，随后是小肠平滑肌细胞的长期肥大反应。平滑肌肌球蛋白重链、α-肌动蛋白和γ-肌动蛋白的表达开始下降，然后随着肥厚的发展而增加。Myocardin的表达先降低后升高，而Kruppel样因子(KLF)4和KLF5的表达则先升高后降低。血清反应因子(SRF)的表达最初降低，然后随着肥厚的发展恢复到假手术水平。SRF与平滑肌MHC和α-肌动蛋白启动子的结合最初减少，但随着肥厚的发展而增加到假手术水平以上。ELK-1与平滑肌肌球蛋白重链和α-肌动蛋白启动子的结合最初增加，然后随着肥大的发展降低到假手术水平。C-fos的表达最初增加，这与SRF/Elk-1与c-fos启动子结合增加有关。ELK-1磷酸化抑制剂U-0126可抑制c-fos表达的增加。这些发现表明小肠平滑肌对肠梗阻的动态反应包括在分化、增殖和肥大表型之间的转换。这些结果表明，SRF、myocardin、Elk-1和c-fos之间的表达和相互作用的变化在机械性梗阻后小肠平滑肌的表型转换中起着关键作用。
Intestinal obstructions lead to a variety of motility disorders. Small intestine smooth muscles undergo dramatic phenotypic changes in response to obstruction, but the underlying molecular mechanisms are unknown. Using RT-PCR, ChIP, Re-ChIP, and Western blots, we examined the effect of small bowel mechanical obstruction on smooth muscle gene expression. Obstruction caused a transient hyperplasia, followed by a prolonged hypertrophic response of small intestine smooth muscle cells. Smooth muscle myosin heavy chain (MHC), α-actin, and γ-actin expression decreased initially, and then increased as hypertrophy developed. Myocardin expression decreased initially and then increased, while kruppel-like factors (KLF)4 and KLF5 expression increased initially, and then decreased. Serum response factor (SRF) expression decreased initially, and then recovered to sham-operated levels as hypertrophy developed. SRF binding to smooth muscle MHC and α-actin promoters decreased initially, but then increased above sham-operated levels as hypertrophy developed. Elk-1 binding to smooth muscle myosin heavy chain and α-actin promoters increased initially, and then decreased to sham-operated levels as hypertrophy developed. c-fos expression increased initially, which was associated with increased SRF/Elk-1 binding to the c-fos promoter. The Elk-1 phosphorylation inhibitor U-0126 inhibited the increase in c-fos expression. These findings indicate a dynamic response of small intestine smooth muscles to bowel obstruction involving switching between differentiated, proliferative, and hypertrophic phenotypes. These results suggest that changes in the expression and interactions between SRF, myocardin, Elk-1, and c-fos play key roles in the phenotypic switching of small intestine smooth muscles in response to mechanical obstruction.
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