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J. Biol. Chem., Vol. 282, Issue 11, 8325-8331, March 16, 2007

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Post-transcriptional Up-regulation of ADAM17 upon Epidermal Growth Factor Receptor Activation and in Breast Tumors^*

From the Medical Oncology Research Program, Vall d'Hebron University Hospital Research Institute, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain

ADAM17 is a transmembrane metalloprotease involved in the proteolytic release of the extracellular domain of many cell surface molecules, a process known as ectodomain shedding. Despite its likely participation in tumor progression and its current consideration as a therapeutic target, very little is known about the regulation of the expression of ADAM17. Here we show that long term treatment with epidermal growth factor (EGF) leads to a marked increase in the levels of ADAM17. EGF receptor activation does not affect the levels of the mRNA that encodes for, or the rate of synthesis of, ADAM17 but increases its half-life. The effect of EGF is biologically relevant because it increases the shedding of several substrates of ADAM17, including the desmosomal cadherin Dsg-2. Analysis of protein and mRNA levels in mammary tumor samples shows that in vivo the levels of ADAM17 can also be controlled post-transcriptionally. Finally, we show that both the shed extracellular domains of Dsg-2 and ADAM17 are frequently expressed in tumors, further supporting the participation of the metalloprotease in malignant progression.

Received for publication, September 13, 2006 , and in revised form, December 29, 2006.

^* This work was supported by Grant BM 05-208-00 from Fundació "La Caixa," Grant FP6-503228 from the European Commission, and Grant SAF2005-03939 from the Spanish Ministry of Education and Science (to J. A.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ To whom correspondence should be addressed. Tel.: 34-93-274-6026; Fax: 34-93-274-6026; E-mail: jarribas{at}ir.vhebron.net.

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