生物谷报道： 厦门大学生物医学研究院许华曦教授和张云武教授最新研究发现，在Alzheimer老年痴呆症发病过程中起关键性作用的gamma分泌酶具有抑制肿瘤的作用。该研究成果在世界上第一次比较深入地揭示了老年痴呆症和癌症之间的联系，对这两个热门领域的研究都将产生巨大的影响，具有重要的生理意义和对疾病治疗的指导作用。该研究成果目前已被代表国际生物医学研究最高水平之一的杂志PNAS收录并发表。
许华曦教授和张云武教授的研究一方面提示通过抑制gamma分泌酶活性的手段治疗Alzheimer老年痴呆有可能增加病人患皮肤癌的风险；另一方面也比较详细地阐明了AICD和PS/gamma分泌酶活性能够下调EGFR这一重要的肿瘤相关基因的表达，为治疗癌症开辟了一条崭新的途径。
该发现发表后在国际生物医学科学研究领域激起了极大地反响和广泛的关注。Newswise、ScienceDaily、Scienceblog、United Press International等众多最权威国际科研新闻门户网站竞相报导，称该其为“爆炸性的发现”。
本研究课题是由厦门大学生物医学研究院与美国加州Burnham医学研究所合作完成。其中张云武教授为该论文第一作者和第一通讯作者；另外厦门大学生物医学研究院博士研究生王瑞山和硕士研究生张含也作为共同作者参与了该课题的研究。（引自厦门大学）
原始出处:
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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