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This Article Full Text Full Text (PDF) All Versions of this Article: JOE-08-0005v1 198/2/291    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Krause, K. Articles by Fuhrer, D. PubMed PubMed Citation Articles by Krause, K. Articles by Fuhrer, D.

Division of Endocrinology, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Str. 27, D-04103 Leipzig, Germany¹ Institute of Pathology and Neuropathology, University of Duisburg-Essen, Hufelandstraße 55, D-45122 Essen, Germany² Institute of Pathology, University of Leipzig, Liebigstraße 26, D-04103 Leipzig, Germany³ Department of Surgery, University of Halle, Ernst-Grube-Straße 40, D-06120 Halle, Germany

(Correspondence should be addressed to D Fuhrer; Email: fued{at}medizin.uni-leipzig.de)

We have recently found an increased expression of amyloid precursor protein (APP) in cold thyroid nodules that are difficult to classify as a truly benign thyroid neoplasm or a lesion with the potential for further dedifferentiation. Since differences in APP activity have been found in other human cancers, we asked whether thyroid carcinogenesis might be associated with an altered APP expression and function. APP regulation was studied in vitro in differentiated (FRTL-5) and dedifferentiated follicular thyroid carcinomas (FTC-133) thyroid cells after specific inhibition or activation of the cAMP-PKA, the PI3K/AKT or the protein kinase c (PKC) cascades. In vivo analysis of APP expression and downstream signalling was performed in benign and malignant thyroid tissues. We found that upregulation of APP expression and sAPP secretion is induced by TSH in differentiated thyroid cells and by insulin in thyroid cancer cells. PKC is a strong activator of APP cleavage and in FTC-133 confers prolonged release of the APP ectodomain. FTC-133 but not FRTL-5 cells show a prominent cell surface expression of the APP ectodomain, which has been suggested to function as an autocrine growth factor. Thyroid cancers are characterized by APP upregulation, increased membrane targeting of the APP ectodomain and significantly increased mRNA levels of the APP scaffold proteins JIP1, ShcA and Fe65.