Henckels Eric, Prywes Ron
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
F1000Res. 2013 Oct 29;2:229. doi: 10.12688/f1000research.2-229.v1. eCollection 2013.
Matrix Metallopeptidase 1 (MMP-1) expression has repeatedly been correlated to tumorigenesis and metastasis. Yet, MMP-1 regulation in a metastatic context remains largely unknown. Here we confirm differential MMP-1 expression in mammary carcinoma cells with varied metastatic potentials. We show that MMP-1 expression is regulated by an AP-1 element in its promoter in highly metastatic MDA-MB-231 mammary carcinoma cell derivatives. Fra-1, an AP-1 family transcription factor, differentially binds this element in highly metastatic cells compared to low metastatic cells and is required for MMP-1 expression. Overexpression of Fra-1 also caused increased MMP-1 expression. Fra-1 mRNA levels are unchanged in the cell variants, however its protein levels are higher in the metastatic cells. While there was no change in Fra-1 protein degradation rates, protein synthesis of Fra-1 was increased in the metastatic cell variant. These results demonstrate that Fra-1 and MMP-1 levels are differentially regulated in metastatic cell variants at the level of Fra-1 protein translation. Consistent with the importance of Fra-1 for tumor growth, we found that Fra-1 overexpression was sufficient to increase cell motility and anchorage independent growth. These results suggest that increased Fra-1 translation is critical for regulation of MMP-1 and tumor cell metastasis.
基质金属肽酶1（MMP-1）的表达多次与肿瘤发生和转移相关。然而，在转移背景下MMP-1的调控仍 largely unknown。在这里，我们证实了具有不同转移潜能的乳腺癌细胞中MMP-1的差异表达。我们表明，在高转移性MDA-MB-231乳腺癌细胞衍生物中，MMP-1的表达受其启动子中的AP-1元件调控。Fra-1是一种AP-1家族转录因子，与低转移性细胞相比，它在高转移性细胞中差异结合该元件，并且是MMP-1表达所必需的。Fra-1的过表达也导致MMP-1表达增加。Fra-1的mRNA水平在细胞变体中没有变化，但其蛋白水平在转移性细胞中更高。虽然Fra-1蛋白降解率没有变化，但Fra-1的蛋白合成在转移性细胞变体中增加。这些结果表明，在Fra-1蛋白翻译水平上，Fra-1和MMP-1水平在转移性细胞变体中受到差异调控。与Fra-1对肿瘤生长的重要性一致，我们发现Fra-1的过表达足以增加细胞运动性和锚定非依赖性生长。这些结果表明，Fra-1翻译增加对于MMP-1和肿瘤细胞转移的调控至关重要。
