生物谷報(bào)道： 廈門(mén)大學(xué)生物醫(yī)學(xué)研究院許華曦教授和張?jiān)莆浣淌谧钚卵芯堪l(fā)現(xiàn),，在Alzheimer老年癡呆癥發(fā)病過(guò)程中起關(guān)鍵性作用的gamma分泌酶具有抑制腫瘤的作用,。該研究成果在世界上第一次比較深入地揭示了老年癡呆癥和癌癥之間的聯(lián)系,，對(duì)這兩個(gè)熱門(mén)領(lǐng)域的研究都將產(chǎn)生巨大的影響,，具有重要的生理意義和對(duì)疾病治療的指導(dǎo)作用,。該研究成果目前已被代表國(guó)際生物醫(yī)學(xué)研究最高水平之一的雜志PNAS收錄并發(fā)表,。
許華曦教授和張?jiān)莆浣淌诘难芯恳环矫嫣崾就ㄟ^(guò)抑制gamma分泌酶活性的手段治療Alzheimer老年癡呆有可能增加病人患皮膚癌的風(fēng)險(xiǎn),；另一方面也比較詳細(xì)地闡明了AICD和PS/gamma分泌酶活性能夠下調(diào)EGFR這一重要的腫瘤相關(guān)基因的表達(dá),，為治療癌癥開(kāi)辟了一條嶄新的途徑,。
該發(fā)現(xiàn)發(fā)表后在國(guó)際生物醫(yī)學(xué)科學(xué)研究領(lǐng)域激起了極大地反響和廣泛的關(guān)注。Newswise,、ScienceDaily,、Scienceblog、United Press International等眾多最權(quán)威國(guó)際科研新聞門(mén)戶網(wǎng)站競(jìng)相報(bào)導(dǎo),，稱該其為“爆炸性的發(fā)現(xiàn)”,。
本研究課題是由廈門(mén)大學(xué)生物醫(yī)學(xué)研究院與美國(guó)加州Burnham醫(yī)學(xué)研究所合作完成。其中張?jiān)莆浣淌跒樵撜撐牡谝蛔髡吆偷谝煌ㄓ嵶髡?；另外廈門(mén)大學(xué)生物醫(yī)學(xué)研究院博士研究生王瑞山和碩士研究生張含也作為共同作者參與了該課題的研究,。（引自廈門(mén)大學(xué)）
原始出處:
Published online before print June 7, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0703903104
OPEN ACCESS ARTICLE
Medical Sciences
Presenilin/-secretase-dependent processing of -amyloid precursor protein regulates EGF receptor expression
( Alzheimer's disease | -amyloid precursor protein intracellular domain | transcriptional regulation | tumorigenesis )
Yun-wu Zhang *, Ruishan Wang *, Qiang Liu , Han Zhang *, Francesca-Fang Liao *, and Huaxi Xu *¶
*Center for Neuroscience and Aging, Burnham Institute for Medical Research, La Jolla, CA 92037; Institute for Biomedical Research, Xiamen University, Xiamen 361005, China; and Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110
Communicated by S. J. Singer, University of California at San Diego, La Jolla, CA, April 27, 2007 (received for review March 5, 2007)
Abstract
Presenilins (PS, PS1/PS2) are necessary for the proteolytic activity of -secretase, which cleaves multiple type I transmembrane proteins including Alzheimer's -amyloid precursor protein (APP), Notch, ErbB4, etc. Cleavage by PS/-secretase releases the intracellular domain (ICD) of its substrates. Notch ICD translocates into the nucleus to regulate expression of genes important for development. However, the patho/physiological role of other ICDs, especially APP ICD (AICD), in regulating gene expression remains controversial because evidence supporting this functionality stems mainly from studies performed under supraphysiological conditions. EGF receptor (EGFR) is up-regulated in a wide variety of tumors and hence is a target for cancer therapeutics. Abnormal expression/activation of EGFR contributes to keratinocytic carcinomas, and mice with reduced PS dosages have been shown to develop skin tumors. Here we demonstrate that the levels of PS and EGFR in the skin tumors of PS1+/-/PS2-/- mice and the brains of PS1/2 conditional double knockout mice are inversely correlated. Deficiency in PS/-secretase activity or APP expression results in a significant increase of EGFR in fibroblasts. Importantly, we show that AICD mediates transcriptional regulation of EGFR. Furthermore, we provide in vivo evidence demonstrating direct binding of endogenous AICD to the EGFR promoter. Our results indicate an important role of PS/-secretase-generated APP metabolite AICD in gene transcription and in EGFR-mediated tumorigenesis.
Fig. 1. PS deficiency results in tumorigenesis and an increase in EGFR level. (A) S1//PS2/ mice develop skin tumors during aging. (Left Upper) An 18-month-old PS1//PS2/ mouse showing massive skin lesions compared with its littermate control. (Left Lower) A representative skin lesion on the back of an 18-month-old PS1//PS2/ mouse. (Right) Hematoxylin/eosin
staining of PS1//PS2/ mouse skin tumor showing expanded dermis withinfiltrating clusters of neoplastic squamous epithelial cells (i), which are characteristic of locally invasive squamous cell carcinoma. (Scale bar: 250 m.) (B) The level of EGFR is inversely correlated to the level of PS1 in tumors from PS1//PS2/ mice. Equal amounts of protein lysates of six tumor amples derived from different PS1//PS2/ mice were analyzed by electrophoresison 4–20% SDS/PAGE gels and immunoblotted with antibodies against EGFR, PS1 N-terminal fragment, and -actin (as loading control). (C) The level of EGFR is markedly increased in the brains of PS1/PS2 conditionalDKO(PS cDKO) mice. Equal amounts of protein lysates from three brain samples derived from PS cDKO mice at 6 months of age and three brain samples from littermate
controls were analyzed by SDS/PAGE and immunoblotted with antibodies against EGFR and -tubulin. Quantification was done by comparing the densitometric values. Data represent eansSD of EGFR level normalized to that of -tubulin and relative to that of control. *, P 0.041, PS cDKO vs. control (n 3).
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