Carcinogenesis, Vol. 23, No. 1, 25-33,
January 2002
© 2002 Oxford University Press
CANCER BIOLOGY |
Expression of mutant thyroid hormone nuclear receptors is associated with human renal clear cell carcinoma
Laboratory of Molecular Biology, National Cancer Institute, 37 Convent Drive MSC 4255,
1 Laboratory of Biochemistry and Genetics, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-4255, USA,
2 Department of Endocrinology, Medical Research Center, Polish Academy of Sciences and
3 Department of Biochemistry, Medical Center of Postgraduate Education, Warsaw, Poland
Thyroid hormone (T3) regulates proliferation and differentiation of cells, via its nuclear receptors (TRs). These processes have been shown to be abnormally regulated during carcinogenesis. We have previously found aberrant expression of TR
and TRß mRNAs in renal clear cell carcinoma (RCCC), suggesting possible involvement of TRs in the carcinogenesis of RCCC. To understand the molecular actions of TRs in RCCC, cDNAs for TRß1 and TR1 were cloned from 22 RCCC tissues and 20 surrounding normal tissues. Mutations were found in seven TRß1 and three TR1 cDNAs. Two TRß1 cDNAs had a single mutation, while five TRß1 and three TR1 had two or three mutations. Most of the mutations were localized in the hormone-binding domain. Using the TRs prepared by in vitro transcription/translation, we found that these mutations led to a loss of T3 binding activity and/or impairment in binding to thyroid hormone response elements (TREs). Furthermore, nuclear extracts from RCCC tissues also exhibited impairment in binding to TREs. These results indicate that the normal functions of TRs in RCCC tissues were impaired. Together with the aberrant expression patterns, these mutated TRs could contribute to the carcinogenesis of RCCC.
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