p53因編碼一種分子質(zhì)量為53kDa的蛋白質(zhì)而得名,，是一種抗癌基因,。其表達(dá)產(chǎn)物為基因調(diào)節(jié)蛋白（P53蛋白），當(dāng)DNA受到損傷時(shí)表達(dá)產(chǎn)物急劇增加，可抑制細(xì)胞周期進(jìn)一步運(yùn)轉(zhuǎn),。一旦p53基因發(fā)生突變,，P53蛋白失活，細(xì)胞分裂失去節(jié)制,，發(fā)生癌變,。目前已知人類癌癥中約有一半是由于該基因發(fā)生突變失活。
在應(yīng)答于致癌壓力時(shí),，腫瘤抑制蛋白ARF激活了p53,，然而核糖體蛋白L11是在應(yīng)答核糖體壓力時(shí)誘導(dǎo)p53。
這兩種蛋白都結(jié)合在不重疊的MDM2的中心區(qū)域,，并抑制MDM2對p53的活性,。
然而，這兩條信號通路是否有功能上的聯(lián)系還不可知,。近日,，美國印第安納大學(xué)醫(yī)學(xué)院的Hua Lu等人發(fā)現(xiàn)，在體外及細(xì)胞內(nèi),，ARF直接結(jié)合到L11,，然后與MDM2及p53形成了一個(gè)復(fù)合體。
L11可以協(xié)同的增強(qiáng)ARF誘導(dǎo)的p53的轉(zhuǎn)錄活性及細(xì)胞周期停滯,。后續(xù)實(shí)驗(yàn)發(fā)現(xiàn)：敲除L11會(huì)降低ARF介導(dǎo)的p53的積聚,，緩和ARF誘導(dǎo)的細(xì)胞周期停滯，這些證據(jù)支持了這些結(jié)論,。有趣的是,，ARF的過表達(dá)提升了無核糖體的L11的水平，增強(qiáng)了L11與MDM2及p53的相互作用,。
這些結(jié)果表明：ARF至少部分的通過核糖體壓力的誘導(dǎo)來激活p53,，結(jié)果導(dǎo)致L11對MDM2的抑制作用，這表明了ARF-MDM2-p53與L11-MDM2-p53通路是功能上相關(guān)的,。相關(guān)論文發(fā)表在3月30日的The Journal of Biological Chemistry,。（生物谷Deepblue編譯）
doi: 10.1074/jbc.M111.311902
PMC:
PMID:
Physical and functional interaction between ribosomal protein L11 and the tumor suppressor ARF
Mu-Shui Dai, Kishore B. Challagundla, Xiao-Xin Sun, Lakshmi Reddy Palam, Shelya X. Zeng, Ronald C. Wek and Hua Lu.
The ARF tumor suppressor protein activates p53 in response to oncogenic stress, whereas ribosomal protein L11 induces p53 following ribosomal stress.Both proteins bind to central, albeit non-overlapping, regions of MDM2 and suppress MDM2 activity towards p53.However, it is not known whether the two pathways are functionally connected. Here we show that ARF directly binds to L11 in vitro and in cells, which then forms a complex with MDM2 and p53.L11 collaboratively enhances ARF-induced p53 transcriptional activity and cell cycle arrest. Supporting these results, knocking down L11 reduces ARF-mediated p53 accumulation and alleviates ARF-induced cell cycle arrest. Interestingly, overexpression of ARF increases the levels of ribosome-free L11 and enhances the interaction of L11 with MDM2 and p53.
These results demonstrate that ARF activates p53, at least partly by induction of ribosomal stress, which results in L11 suppression of MDM2, and suggest that the ARF-MDM2-p53 and the L11-MDM2-p53 pathways are functionally connected.
