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首页> 外文期刊>Cell cycle >JAZ mediates G1 cell cycle arrest by interacting with and inhibiting E2F1.
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JAZ mediates G1 cell cycle arrest by interacting with and inhibiting E2F1.

机译：JAZ通过与E2F1相互作用并抑制E2F1介导G1细胞周期停滞。

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We discovered and reported JAZ as a unique dsRNA binding zinc finger protein that functions as a direct, positive regulator of p53 transcriptional activity to mediate G1 cell cycle arrest in a mechanism involving upregulation of the p53 target gene, p21. We now find that JAZ can also negatively regulate the cell cycle in a novel, p53-independent mechanism resulting from the direct interaction with E2F1, a key intermediate in regulating cell proliferation and tumor suppression. JAZ associates with E2F1's central DNA binding/dimerization region and its C-terminal transactivation domain. Functionally, JAZ represses E2F1 transcriptional activity in association with repression of cyclin A expression and inhibition of G1/S transition. This mechanism involves JAZ-mediated inhibition of E2F1's specific DNA binding activity. JAZ directly binds E2F1 in vitro in a dsRNA-independent manner, and JAZ's dsRNA binding ZF domains, which are necessary for localizing JAZ to the nucleus, are required for repression of transcriptional activity in vivo. Importantly for specificity, siRNA-mediated knockdown cells from G1 arrest, indicating a necessary role for JAZ in this transition. Although JAZ can directly inhibit E2F1 activity independently of p53, if functional p53 is expressed, JAZ may exert a more potent inhibition of cell cycle following growth factor withdrawal. Therefore, JAZ plays a dual role in cell cycle regulation by both repressing E2F1 transcriptional activity and activating p53 to facilitate efficient growth arrest in response to cellular stress, which may potentially be exploited therapeutically for tumor growth inhibition.
机译：我们发现并报道了JAZ是一种独特的dsRNA结合锌指蛋白，可作为p53转录活性的直接，正调节剂，以介导p53靶基因p21上调的机制介导G1细胞周期停滞。现在我们发现，JAZ还可以通过与E2F1（调节细胞增殖和抑制肿瘤的关键中间产物）直接相互作用而产生的一种新型的，独立于p53的机制来负调控细胞周期。 JAZ与E2F1的中央DNA结合/二聚区及其C末端反式激活域相关。在功能上，JAZ抑制E2F1转录活性，同时抑制细胞周期蛋白A的表达和抑制G1 / S过渡。该机制涉及JAZ介导的E2F1特异性DNA结合活性的抑制。 JAZ在体外以不依赖dsRNA的方式直接结合E2F1，而JAZ的dsRNA结合ZF结构域是将JAZ定位于细胞核所必需的，是体内抑制转录活性所必需的。对于特异性而言，重要的是siRNA介导的G1阻滞细胞被阻滞，表明JAZ在此过渡过程中的必要作用。尽管JAZ可以独立于p53直接抑制E2F1活性，但如果表达功能性p53，则JAZ可能在撤消生长因子后对细胞周期产生更有效的抑制作用。因此，JAZ通过抑制E2F1转录活性和激活p53来促进对细胞应激的有效生长停滞，从而在细胞周期调控中起双重作用，这可能在治疗上可用于肿瘤生长抑制。

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