Cytoplasmic YY1 is associated with increased smooth muscle-specific gene expression - Implications for neonatal pulmonary hypertension
Cytoplasmic YY1 is associated with increased smooth muscle-specific gene expression - Implications for neonatal pulmonary hypertension
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DOI：
10.1016/s0002-9440(10)61236-9
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发表时间：
2005-12-01
影响因子：
6
通讯作者：
Kemp, PR
中科院分区：
文献类型：
--
作者：
Favot, L;Hall, SM;Kemp, PR
出生后，肺弹性动脉的腔内血管SMCs发生短暂的肌动蛋白细胞骨架。重塑以及细胞去分化和增殖。血管平滑肌表型受血清反应因子调节，而血清反应因子本身部分受负调节因子YY1调节。因此，我们研究了YY1在正常新生仔猪和新生儿肺动脉高压仔猪动脉中的亚细胞定位。我们发现YY1的定位在发育过程中发生了变化，γ -平滑肌肌动蛋白的表达与细胞质而非细胞核YY1的表达相关。体外对YY1定位的调控分析表明，聚合的γ -肌动蛋白将EGFP-YY1隔离在细胞质中，而YY1激活c-myc启动子活性被LIM激酶抑制，从而增加了肌动蛋白的聚合。与这些数据一致的是，sirna介导的YY1在C2C12细胞中的下调增加了sm22 - α的表达，抑制了细胞的增殖。因此，肌动蛋白聚合控制亚细胞YY1定位，这有助于正常肺动脉发育中血管SMC的增殖和分化。在没有肌动蛋白解聚的情况下，YY1不能重新定位到细胞核，这种重新定位的缺乏可能有助于肺动脉高压的病理生物学。
Immediately after birth the adluminal vascular SMCs of the pulmonary elastic arteries undergo transient actin cytoskeletal. remodeling as well as cellular dedifferentiation and proliferation. Vascular smooth muscle phenotype is regulated by serum response factor, which is itself regulated in part by the negative regulator YY1. We therefore studied the subcellular localization of YY1 in arteries of normal newborn piglets and piglets affected by neonatal pulmonary hypertension. We found that YY1 localization changed during development and that expression of gamma-smooth muscle actin correlated with expression of cytoplasmic rather than nuclear YY1. Analysis of the regulation of YY1 localization in vitro demonstrated that polymerized gamma-actin sequestered EGFP-YY1 in the cytoplasm and that YY1 activation of c-myc promoter activity was inhibited by LIM kinase, which increases actin polymerization. Consistent with these data siRNA-mediated down-regulation of YY1 in C2C12 cells increased SM22-alpha expression and inhibited cell proliferation. Thus, actin polymerization controls subcellular YY1 localization, which contributes to vascular SMC proliferation and differentiation in normal pulmonary artery development. in the absence of actin depolymerization, YY1 does not relocate to the nucleus, and this lack of relocation may contribute to the pathobiology of pulmonary hypertension.