Regulation of AKR1B1 by thyroid hormone and its receptors.
The objective of this study was to identify genes regulated by thyroid hormone (T(3)) mediated by its receptor (TR) and associated with tumorigenesis. The gene encoding aldo-keto reductase family 1, member B1 (AKR1B1), as previously identified by c-DNA microarray, is known to be up-regulated by T(3) treatment. Enzyme AKR1B1 was elevated roughly 3-fold in HepG2-TRalpha1 cells at the protein level and 4.6-fold increase at the mRNA level after 48 h T(3) treatment. Similar findings were obtained from thyroidectomized rats after T(3) application. To identify and localize the critical TR element (TRE), series deletion of the promoter mutant were constructed and electrophoretic mobility shift assays were carried out. The TRE on the AKR1B1 promoter was localized to the -1099/-1028 region. Further, this study demonstrated that AKR1B1 over-expression in some types of hepatocellular carcinomas (HCCs) is TR-dependent and might play a crucial role in the development of HCC. Thus, T(3) regulates AKR1B1 gene expression via a TRE-dependant mechanism and associates liver cancer.
Liao
Chen-Shin
CS
Department of Biochemistry, Chang-Gung University, Taoyuan, Taiwan, ROC.
Tai
Pei-Ju
PJ
Huang
Ya-Hui
YH
Chen
Ruey-Nan
RN
Wu
Sheng-Ming
SM
Kuo
Lu-Wei
LW
Yeh
Chau-Ting
CT
Tsai
Ming-Ming
MM
Chen
Wei-Jan
WJ
Lin
Kwang-Huei
KH
D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009361:Neoplasm Invasiveness; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020218:Response Elements / Q000235:genetics; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014284:Triiodothyronine / Q000494:pharmacology*
D012333:RNA, Messenger; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D003513:Cycloheximide; D000449:Aldehyde Reductase