MRTF-A/B suppress the oncogenic properties of v-ras- and v-src-mediated transformants.
MRTF-A/B suppress the oncogenic properties of v-ras- and v-src-mediated transformants.
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DOI：
10.1093/carcin/bgq065
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发表时间：
2010-07
期刊：
影响因子：
4.7
通讯作者：
Toshiyuki Yoshio;T. Morita;M. Tsujii;N. Hayashi;K. Sobue
中科院分区：
文献类型：
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作者：
Toshiyuki Yoshio;T. Morita;M. Tsujii;N. Hayashi;K. Sobue
心肌蛋白家族的两个成员，心肌蛋白相关转录因子（MRTF）-A和MRTF-B是血清反应因子（SRF）的共激活物。我们最近报道，MRTF-A/B依赖性地激活几个肌动蛋白细胞骨架/粘着斑基因SRF的转录，从而增强应力纤维和粘着斑的形成。在这里，我们发现，钙调蛋白和原肌球蛋白，SRF/MRTF调节的肌动蛋白细胞骨架蛋白，在大鼠肠上皮（RIE）细胞系，已转化与致癌ras（RIE-ras）或src（RIE-src）相比，其亲本细胞系的水平降低。这些细胞表现出与肌动蛋白细胞骨架紊乱相关的形态异常。RIE-ras和RIE-src细胞中血清刺激的MRTF-A/B核转位被抑制。然而，组成型活性（CA）MRTF-A或MRTF-B的瞬时表达逆转了钙调蛋白和原肌球蛋白的表达水平降低和相关的形态表型。我们从转染的RIE-ras和RIE-src细胞中分离出稳定的CA-MRTF-A表达细胞系，发现它们的钙调蛋白和原肌球蛋白水平接近未转化的RIE细胞。它们的形态也是正常的，具有扁平的细胞形状和发育良好的应力纤维。CA-MRTF-A表达RIE-ras和RIE-src系在体外也显示出比其转化的亲本细胞更低的侵袭性和锚定非依赖性生长。在体内，CA-MRTF-A表达抑制肿瘤形成并减少肝转移。因此，我们得出结论，MRTF-A/B是肿瘤进展和转移的有效抑制因子，可能是肿瘤治疗的良好靶点。
Two members of the myocardin protein family, myocardin-related transcription factor (MRTF)-A and MRTF-B are co-activators of serum response factor (SRF). We recently reported that MRTF-A/B activates the transcription of several actin cytoskeletal/focal adhesion genes SRF dependently, thereby enhancing the formation of stress fibers and focal adhesions. Here, we showed that the levels of caldesmon and tropomyosin, both SRF/MRTF-regulated actin cytoskeletal proteins, were reduced in rat intestinal epithelial (RIE) cell lines that had been transformed with oncogenic ras (RIE-ras) or src (RIE-src) compared with their parental cell line. These cells exhibited morphological abnormalities associated with a disorganized actin cytoskeleton. The serum-stimulated nuclear translocation of MRTF-A/B was suppressed in the RIE-ras and RIE-src cells. However, the transient expression of constitutively active (CA) MRTF-A or MRTF-B reversed the reduced expression levels of caldesmon and tropomyosin and the associated morphological phenotypes. We isolated stable CA-MRTF-A-expressing cell lines from transfected RIE-ras and RIE-src cells and found that their levels of caldesmon and tropomyosin were close to those of untransformed RIE cells. Their morphologies were also normal, with a flattened cell shape and well-developed stress fibers. The CA-MRTF-A-expressing RIE-ras and RIE-src lines also showed lower invasiveness and anchorage-independent growth than their transformed parental cells, in vitro. In vivo, CA-MRTF-A expression suppressed tumor formation and reduced liver metastases. Therefore, we concluded that MRTF-A/B are potent repressors of cancer progression and metastasis and may be good targets for cancer therapy.