Abstract
Children exposed to radioactive iodine as a consequence of the Chernobyl reactor accident have an increased risk of papillary thyroid carcinomas (PTC). The predominant molecular lesions in these tumors are rearrangements of the RET receptor tyrosine kinase (tk). Here we report on two novel types of RET rearrangement, PTC6 and 7, and describe the fusion products and the ret fused gene (rfg) proteins. Like the other rfg proteins identified so far they are ubiquitously expressed, not membrane-bound and contain coiled coil domains required for constitutive activation of the ret tk domain. In the PTC6 rearrangement the ret tk domain is fused to the aminoterminal part of the human transcription intermediary factor htif 1. In the PTC7 rearrangement the ret tk domain is fused to a novel protein that is strongly related to htif1. Like htif1 it contains a RBCC motif (ring finger, B boxes, coiled coil domain) located in the aminoterminal part and a phd finger and a bromodomain in the carboxyterminal part. Htif1 and related proteins are transcription coactivators for nuclear receptors, thus participating in controlling cellular development, differentiation and homeostasis. This is the first report on their involvement in human thyroid carcinogenesis.
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Abbreviations
- GDNF:
-
glial cell derived neurotrophic factor
- Htif:
-
human transcription intermediary factor
- PTC:
-
papillary thyroid carcinoma
- rfg:
-
ret fused gene
- tk:
-
tyrosine kinase
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Acknowledgements
We thank Professor Demidchik, Minsk, Belarus, and Professor Lengfelder, Munich, Germany, for generously providing tumor samples and patients data. We are grateful to Michael Ruiter, Dr Sibylle Liebmann, Rita Koch and Sigrid Madsen for excellent technical assistance and to the Otto Hug-Strahleninstitut and Christine Frenzel for support of this work. This work was supported by grants (to HMR) from Dr Mildred Scheel-Stiftung für Krebsforschung, Bonn, Germany and from Wilhelm Sander-Stiftung, Neuburg an der Donau, Germany.
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Klugbauer, S., Rabes, H. The transcription coactivator HTIF1 and a related protein are fused to the RET receptor tyrosine kinase in childhood papillary thyroid carcinomas. Oncogene 18, 4388–4393 (1999). https://doi.org/10.1038/sj.onc.1202824
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DOI: https://doi.org/10.1038/sj.onc.1202824
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