來(lái)自臺(tái)灣中央研究院的楊泮池院士領(lǐng)銜的研究團(tuán)隊(duì)發(fā)現(xiàn)了p53的抑癌新機(jī)制。P53一直是為人熟知的抑癌基因，人類(lèi)50%的癌癥與該基因有關(guān),，包括,，肝癌,、肺癌,、胃癌、食道癌,、結(jié)腸癌,、卵巢癌等等。然而,，目前關(guān)于p53與癌癥的研究只是p53機(jī)制的冰山一角,，人類(lèi)離獲得p53的全景還有一定的距離。
楊泮池領(lǐng)銜的研究團(tuán)隊(duì)由臺(tái)灣大學(xué)醫(yī)學(xué)院,，國(guó)防醫(yī)學(xué)院,、及成大學(xué)醫(yī)學(xué)院，中央研究院的科研人員組成,。他們的研究發(fā)現(xiàn),，在正常的細(xì)胞中，p53及其下游分子MDM2可以調(diào)控促癌轉(zhuǎn)移分子Slug,，透過(guò)形成p53-MDM2-Slug復(fù)合體改變Slug的穩(wěn)定性,，因而抑制癌細(xì)胞轉(zhuǎn)移能力。然而,，一旦p53發(fā)生變異,，突變的p53即喪失控制Slug蛋白穩(wěn)定性的能力,，細(xì)胞內(nèi)不斷累積的Slug蛋白促使癌細(xì)胞獲得強(qiáng)大的轉(zhuǎn)移能力，最終導(dǎo)致癌細(xì)胞擴(kuò)散至全身,。
楊泮池院士指出,，除了細(xì)胞生物學(xué)的基礎(chǔ)研究之外，p53-MDM2-Slug調(diào)控路徑同時(shí)也在臨床肺癌檢測(cè)中獲得驗(yàn)證,，肺癌的擴(kuò)散路徑正是p53-MDM2-Slug通路,。
研究小組還應(yīng)用siRNA阻斷變異的p53-MDM2-Slug路徑，用以防止癌癥擴(kuò)散,。同時(shí),，還與旅美中央院院士李國(guó)雄合作，利用他研發(fā)的專(zhuān)利化合物進(jìn)行細(xì)胞試驗(yàn),，研究結(jié)果證實(shí)低劑量的該化合物就能阻斷Slug路徑,。(生物谷Bioon.com)
生物谷推薦原始出處：
Nature Cell Biology 17 May 2009 doi:10.1038/ncb1875
p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug
Shu-Ping Wang1, Wen-Lung Wang1, Yih-Leong Chang2, Chen-Tu Wu2, Yu-Chih Chao1, Shih-Han Kao3, Ang Yuan4, Chung-Wu Lin5, Shuenn-Chen Yang6, Wing-Kai Chan7, Ker-Chau Li8, Tse-Ming Hong9,11 & Pan-Chyr Yang4,6,10,11
The tumour suppressor p53 is known to prevent cancer progression by inhibiting proliferation and inducing apoptosis of tumour cells. Slug, an invasion promoter, exerts its effects by repressing E-cadherin transcription. Here we show that wild-type p53 (wtp53) suppresses cancer invasion by inducing Slug degradation, whereas mutant p53 may stabilize Slug protein. In non-small-cell lung cancer (NSCLC), mutation of p53 correlates with low MDM2, high Slug and low E-cadherin expression. This expression profile is associated with poor overall survival and short metastasis-free survival in patients with NSCLC. wtp53 upregulates MDM2 and forms a wtp53–MDM2–Slug complex that facilitates MDM2-mediated Slug degradation. Downregulation of Slug by wtp53 or MDM2 enhances E-cadherin expression and represses cancer cell invasiveness. In contrast, mutant p53 inactivates Slug degradation and leads to Slug accumulation and increased cancer cell invasiveness. Our findings indicate that wtp53 and p53 mutants may differentially control cancer invasion and metastasis through the p53–MDM2–Slug pathway.
1 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan.
2 Department of Pathology and Graduate Institute of Pathology, National Taiwan University, Taipei 10043, Taiwan.
3 Graduate Institute of Molecular Biology, College of Medicine, National Taiwan University, Taipei 10043, Taiwan.
4 Department of Internal Medicine, National Taiwan University Hospital, Taipei 10043, Taiwan.
5 Department of Pathology, National Taiwan University Hospital, Taipei 10043, Taiwan.
6 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
7 Department of Medical Research, National Taiwan University Hospital, Taipei 10043, Taiwan.
8 Institute of Statistical Science, Academia Sinica, Taipei, 11529, Taiwan.
9 Institute of Clinical Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
10 NTU Center for Genomic Medicine, College of Medicine, National Taiwan University, Taipei 10043, Taiwan.
11 These authors contributed equally to this work.
