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首页> 外文期刊>Oncogene >Human tumor suppressor p14ARF negatively regulates rRNA transcription and inhibits UBF1 transcription factor phosphorylation
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Human tumor suppressor p14ARF negatively regulates rRNA transcription and inhibits UBF1 transcription factor phosphorylation

机译：人类肿瘤抑制因子p14ARF负调控rRNA转录并抑制UBF1转录因子磷酸化

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The nucleolar Arf protein has been shown to regulate cell cycle through both p53-dependent and -independent pathways. In addition to the well-characterized Arf-mdm2-p53 pathway, several partners of Arf have recently been described that could participate in alternative regulation process. Among those is the nucleolar protein B23/NPM, involved in the sequential maturation of rRNA. p19ARF can interact with B23/NPM in high molecular complexes and partially inhibit the cleavage of the 32S rRNA, whereas the human p14ARF protein has been shown to participate in the degradation of NPM/B23 by the proteasome. These data led to define Arf as a negative regulator of ribosomal RNA maturation. Our recent finding that the human p14ARF protein was able to specifically interact with the rRNA promoter in a p53-independent context, led us to analyse in vitro and in vivo the consequences of this interaction. Luciferase assay and pulse-chase experiments demonstrated that the rRNA transcription was strongly reduced upon p14ARF overexpression. Investigations on potential interactions between p14ARF and the transcription machinery proteins demonstrated that the upstream binding factor (UBF), required for the initiation of the transcriptional complex, was a new partner of the p14ARF protein. We next examined the phosphorylation status of UBF as UBF phosphorylation is required to recruit on the promoter factors involved in the transcriptional complex. Upon p14ARF overexpression, UBF was found hypophosphorylated, thus unable to efficiently recruit the transcription complex. Taken together, these data define a new p53-independent pathway that could regulate cell cycle through the negative control of rRNA transcription.
机译：已显示核仁Arf蛋白通过p53依赖性和非依赖性途径调节细胞周期。除了特征明确的Arf-mdm2-p53途径外，最近还描述了Arf的一些伙伴，它们可能参与替代调控过程。其中包括核仁蛋白B23 / NPM，它与rRNA的顺序成熟有关。 p19ARF可以与高分子复合物中的B23 / NPM相互作用并部分抑制32S rRNA的裂解，而人类p14ARF蛋白已被证明参与蛋白酶体对NPM / B23的降解。这些数据导致将Arf定义为核糖体RNA成熟的负调节剂。我们最近的发现，即人p14ARF蛋白能够在不依赖p53的情况下与rRNA启动子特异性相互作用，这使我们能够在体外和体内分析这种相互作用的后果。荧光素酶测定和脉冲追踪实验表明，在p14ARF过表达后，rRNA转录会大大降低。对p14ARF和转录机制蛋白之间潜在相互作用的研究表明，转录复合物起始所需的上游结合因子（UBF）是p14ARF蛋白的新伴侣。接下来，我们检查了UBF的磷酸化状态，因为需要UBF磷酸化才能募集参与转录复合体的启动子因子。 p14ARF过表达后，发现UBF磷酸化不足，因此无法有效募集转录复合物。综上所述，这些数据定义了一条新的独立于p53的途径，该途径可通过rRNA转录的阴性控制来调节细胞周期。

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