Retinoic acid induces expression of the thyroid hormone transporter, monocarboxylate transporter 8 (Mct8).
Retinoic acid (RA) and thyroid hormone are critical for differentiation and organogenesis in the embryo. Mct8 (monocarboxylate transporter 8), expressed predominantly in the brain and placenta, mediates thyroid hormone uptake from the circulation and is required for normal neural development. RA induces differentiation of F9 mouse teratocarcinoma cells toward neurons as well as extraembryonal endoderm. We hypothesized that Mct8 is functionally expressed in F9 cells and induced by RA. All-trans-RA (tRA) and other RA receptor (RAR) agonists dramatically (>300-fold) induced Mct8. tRA treatment significantly increased uptake of triiodothyronine and thyroxine (4.1- and 4.3-fold, respectively), which was abolished by a selective Mct8 inhibitor, bromosulfophthalein. Sequence inspection of the Mct8 promoter region and 5'-rapid amplification of cDNA ends PCR analysis in F9 cells identified 11 transcription start sites and a proximal Sp1 site but no TATA box. tRA significantly enhanced Mct8 promoter activity through a consensus RA-responsive element located 6.6 kilobases upstream of the coding region. A chromatin immunoprecipitation assay demonstrated binding of RAR and retinoid X receptor to the RA response element. The promotion of thyroid hormone uptake through the transcriptional up-regulation of Mct8 by RAR is likely to be important for extraembryonic endoderm development and neural differentiation. This finding demonstrates cross-talk between RA signaling and thyroid hormone signaling in early development at the level of the thyroid hormone transporter.
Kogai
Takahiko
T
Molecular Endocrinology Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, and the Departments of Medicine and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90073. Electronic address: tkogai@ucla.edu.
Liu
Yan-Yun
YY
Molecular Endocrinology Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, and the Departments of Medicine and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90073.
Richter
Laura L
LL
Molecular Endocrinology Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, and the Departments of Medicine and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90073.
Mody
Kaizeen
K
Molecular Endocrinology Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, and the Departments of Medicine and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90073.
Kagechika
Hiroyuki
H
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.
Brent
Gregory A
GA
Molecular Endocrinology Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, and the Departments of Medicine and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90073. Electronic address: gbrent@ucla.edu.
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004622:Embryo, Mammalian / Q000196:embryology; D007202:Indicators and Reagents / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D027501:Monocarboxylic Acid Transporters; D009928:Organ Specificity / Q000502:physiology; D038081:Organogenesis / Q000502:physiology; D020218:Response Elements / Q000502:physiology*; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013448:Sulfobromophthalein / Q000494:pharmacology; D027981:Symporters; D013974:Thyroxine / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*; D014284:Triiodothyronine / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D047488:Retinoid X Receptors; C484257:Slc16a2 protein, mouse; D027981:Symporters; D014284:Triiodothyronine; D013448:Sulfobromophthalein; D014212:Tretinoin; D013974:Thyroxine