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This version published online on August 5, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0168
Molecular Endocrinology Vol. 0, No. 2004 200401681-
doi:10.1210/me.2004-0168
Copyright © 2004 by the Endocrine Society.
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Submitted on April 21, 2004
Accepted on July 27, 2004

Regulation of STAT1 and STAT1-dependent genes by RET/PTC (rearranged in transformation/papillary thyroid carcinoma) oncogenic tyrosine kinases

Eun Suk Hwang, Dong Wook Kim, Jung Hwan Hwang, Hye Sook Jung, Jae Mi Suh, Young Joo Park, Hyo Kyun Chung, Jung Hun Song, Ki Cheol Park, Su Hyeon Park, Hwan-Jung Yun, Jin Man Kim, and Minho Shong*

Laboratory of Endocrine Cell Biology, National Research Laboratory Program, Department of Internal Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. Department of Pathology, Chungnam National University School of Medicine, Daejeon, 301-721, Korea

* To whom correspondence should be addressed. E-mail: minhos{at}cnu.ac.kr.

Chimeric RET/PTC (rearranged in transformation/papillary thyroid carcinoma) oncoproteins are constitutively active tyrosine kinases found in thyroid papillary carcinoma and non-neoplastic Hashimoto's thyroiditis. Although several proteins have been identified to be substrates of RET/PTC kinases, the pathogenic roles played by RET/PTC in malignant and benign thyroid diseases and the molecular mechanisms that are involved are not fully understood. We found that RET/PTC expression phosphorylates the Y701 residue of STAT1, a type II interferon-responsive protein. RET/PTC-mediated STAT1 phosphorylation requires RET/PTC kinase activity to be intact but other tyrosine kinases, such as Janus kinases or c-Src, are not involved. RET/PTC-induced STAT1 transcriptional activation was not inhibited by suppressor of cytokine signaling (SOCS)-1 or -3, or protein inhibitors of activated STAT3 (PIAS3), but PIAS1 strongly repressed the RET/PTC-induced transcriptional activity of STAT1. RET/PTC-induced STAT1 activation caused IRF-1 expression. We found that STAT1 and IRF-1 cooperated to significantly increase transcription from type IV interferon-{gamma}-responsive promoters of class II transactivator (CIITA) genes. Significantly, cells stably expressing RET/PTC expressed CIITA and showed enhanced de novo membrane expression of MHC class II proteins. Furthermore, RET/PTC1-bearing papillary thyroid carcinoma cells strongly expressed MHC class II (HLA-DR{alpha}) genes while the surrounding normal tissues did not. Thus, RET/PTC is able to phosphorylate and activate STAT1. This may lead to enhanced MHC class II expression, which may explain why the tissues surrounding RET/PTC-positive cancers are infiltrated with lymphocytes. Such immune response-promoting activity of RET/PTC may also relate to the development of Hashimoto's thyroiditis.
Key words: RET/PTC • STAT1 • IRF-1 • CIITA • MHC class II • thyroid




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