Physical interaction and functional antagonism between the RNA polymerase II elongation factor ELL and p53
Physical interaction and functional antagonism between the RNA polymerase II elongation factor ELL and p53
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DOI：
10.1074/jbc.274.24.17003
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发表时间：
1999-06-11
影响因子：
4.8
通讯作者：
Hatakeyama, M
中科院分区：
文献类型：
--
作者：
Shinobu, N;Maeda, T;Hatakeyama, M
Ell最初被鉴定为在急性髓系白血病中与三胸样MLL基因一起易位的基因。最近的研究表明，基因产物ELL作为RNA聚合酶II的延伸因子，通过抑制短暂的停顿来提高RNA聚合酶II的转录速度。以ELL为诱饵，通过酵母双杂交筛选，分离到ELL的特异性相互作用蛋白P53。这种相互作用分别涉及ELL的转录延伸激活结构域和P53的C末端尾部，通过这种相互作用，ELL既抑制了P53的序列特异性反式激活，又抑制了P53的序列非特异性反式抑制，因此，ELL在转录过程中扮演着P53的负调控角色。相反，P53抑制ELL的转录延伸活性，提示P53能够通过控制ELL的活性来调节RNA聚合酶II的一般转录。细胞中ELL水平的升高导致抑制p53依赖的内源性p21的诱导，并在很大程度上保护细胞免受遗传毒性应激诱导的p53介导的凋亡。我们的观察表明，P53和一般转录延伸因子ELL之间存在相互抑制的相互作用，并提出了P53和ELL之间的异常相互作用可能在携带MLL-ELL基因易位的白血病的发生中发挥作用的可能性。
ELL was originally identified as a gene that undergoes translocation with the trithorax-like MLL gene in acute myeloid leukemia. Recent studies have shown that the gene product, ELL, functions as an RNA polymerase II elongation factor that increases the rate of transcription by RNA polymerase II by suppressing transient pausing. Using yeast two-hybrid screening with ELL as bait, we isolated the p53 tumor suppressor protein as a specific interactor of ELL. The interaction involves respectively the transcription elongation activation domain of ELL and the C-terminal tail of p53, Through this interaction, ELL inhibits both sequence-specific transactivation and sequence-independent transrepression by p53, Thus, ELL acts as a negative regulator of p53 in transcription. Conversely, p53 inhibits the transcription elongation activity of ELL, suggesting that p53 is capable of regulating general transcription by RNA polymerase II through controlling the ELL activity. Elevated levels of ELL in cells resulted in the inhibition of p53-dependent induction of endogenous p21 and substantially protected cells from p53-mediated apoptosis that is induced by genotoxic stress. Our observations indicate the existence of a mutually inhibitory interaction between p53 and a general transcription elongation factor ELL and raise the possibility that an aberrant interaction between p53 and ELL may play a role in the genesis of leukemias carrying MLL-ELL gene translocations.