Expression of mutant thyroid hormone nuclear receptors is associated with human renal clear cell carcinoma.
Thyroid hormone (T(3)) 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 TRalpha and TRbeta 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 TRbeta1 and TRalpha1 were cloned from 22 RCCC tissues and 20 surrounding normal tissues. Mutations were found in seven TRbeta1 and three TRalpha1 cDNAs. Two TRbeta1 cDNAs had a single mutation, while five TRbeta1 and three TRalpha1 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 T(3) 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.
Kamiya
Yuji
Y
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, 37 Convent Drive MSC 4255, Bethesda, MD 20892-4255, USA.
Puzianowska-Kuznicka
Monika
M
McPhie
Peter
P
Nauman
Janusz
J
Cheng
Sheue-yann
SY
Nauman
Alicja
A
D018262:Adenocarcinoma, Clear Cell / Q000235:genetics* / Q000378:metabolism; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014284:Triiodothyronine / Q000378:metabolism
D018076:DNA, Complementary; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine