HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 44, 32264-32273, November 2, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/44/32264    most recent M703649200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Li, T. Articles by Wong, P. C. Search for Related Content PubMed PubMed Citation Articles by Li, T. Articles by Wong, P. C. Social Bookmarking                      What's this?

Epidermal Growth Factor Receptor and Notch Pathways Participate in the Tumor Suppressor Function of -Secretase^*

Tong Li¹, Hongjin Wen, Cory Brayton, Pritam Das^¶, Lisa A. Smithson^¶, Abdul Fauq^¶, Xing Fan, Barbara J. Crain, Donald L. Price^||**, Todd E. Golde^¶, Charles G. Eberhart, and Philip C. Wong^**2

From the Departments of Pathology, ^**Neuroscience, ^||Neurology, and Comparative Medicine, The Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205 and the ^¶Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, Florida 32224

-Secretase, a unique aspartyl protease, is required for the regulated intramembrane proteolysis of Notch and APP, pathways that are implicated, respectively, in the pathogenesis of cancer and Alzheimer disease. However, the mechanism whereby reduction of -secretase causes tumors such as squamous cell carcinoma (SCC) remains poorly understood. Here, we demonstrate that -secretase functions in epithelia as a tumor suppressor in an enzyme activity-dependent manner. Notch signaling is down-regulated and epidermal growth factor receptor (EGFR) is activated in SCC caused by genetic reduction of -secretase. Moreover, the level of EGFR is inversely correlated with the level of -secretase in fibroblasts, suggesting that the up-regulation of EGFR stimulates hyperproliferation in epithelia of mice with genetic reduction of -secretase. Supporting this notion is our finding that the proliferative response of fibroblasts lacking -secretase activity is more sensitive when challenged by either EGF or an inhibitor of EGFR as ompared with wild type cells. Interestingly, the up-regulation of EGFR is independent of Notch signaling, suggesting that the EGFR pathway functions in parallel with Notch in the tumorigenesis of SCC. Collectively, our results establish a novel mechanism linking the EGFR pathway to the tumor suppressor role of -secretase and that mice with genetic reduction of -secretase represent an excellent rodent model for clarifying pathogenesis of SCC and for testing therapeutic strategy to ameliorate this type of human cancer.

Received for publication, May 2, 2007 , and in revised form, August 22, 2007.

^* This work was supported by National Institutes of Health NINDS Grants R01 NS45150 and P01 NS047308 (to P. C. W.), NIA Grant P50 AG05146 (to D. L. P.), grants from the Alzheimer's Association (to P. C. W.), Rotary CART Fund (to P. C. W.), Adler Foundation (to T. L.), and the Ellison Medical Foundation (to T. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed. E-mail: tli1{at}jhmi.edu. ² To whom correspondence may be addressed: 558 Ross Research Bldg., 720 Rutland Ave., Baltimore, MD 21205-2196. Tel.: 410-502-5168; Fax: 410-955-9777; E-mail: wong{at}jhmi.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?