EDITORIAL FOCUS
Thyroid hormone action: down novel paths Focus on "Thyroid hormone induces activation of mitogen-activated protein kinase in cultured cells"

Gregory A. Brent

Endocrinology Division, Departments of Medicine and Physiology, University of California, Los Angeles, School of Medicine, West Los Angeles Veterans Affairs Medical Center, Los Angeles, California 90073


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NONGENOMIC ACTIONS OF THYROID HORMONE have long been recognized, although the specific targets and mechanisms that mediate these actions have been difficult to demonstrate (5). The focus of most investigations into thyroid hormone action, however, has been on the nuclear actions of thyroid hormone (2). Specific thyroid hormone nuclear receptors were identified over 25 years ago, but the dramatic expansion of research in this area followed the cloning of the nuclear receptors in 1986. The complexity of nuclear thyroid hormone action [two thyroid hormone receptor (TR) genes, multiple TR isoforms, dimer formation with three forms of the 9-cis-retinoic acid receptor (RXR), and interactions with multiple coactivators and corepressors] has sustained the interest of a large number of investigators performing research in this area (7). A few laboratories, however, have persisted in working on an increasing number of nongenomic actions of thyroid hormone (5).

Nongenomic actions are characterized by onset within minutes, rather than the hours required for genomic actions. Another important and consistent difference between genomic and nongenomic actions has been the thyroid hormone metabolic product required for a response. The nuclear TR has a much higher affinity for triiodothyronine (T3) than any other analog, and thyroxine (T4) has almost no measurable action. For nongenomic effects, T4 is often more active than T3. Other thyroid hormone analogs that have been thought to be completely inactive biologically, such as reverse T3 and T2, have been shown to be active in some nongenomic effects.

The biological processes that are regulated by nongenomic actions are varied and include cellular respiration, cell morphology, vascular tone, and ion homeostasis (5). The cellular targets include the plasma membrane, cytoskeleton, sarcoplasmic reticulum, mitochondria, and contractile elements of vascular smooth muscle. The tissues that have been the subject of most intense study include the nervous system, vascular smooth muscle, and ion transport in the red blood cell. One well-described nongenomic effect of thyroid hormone is regulation of the enzyme 5'-deiodinase type II (D2), which is important for conversion of T4 to T3, especially in the brain and pituitary. Thyroid hormone inhibits D2 by a nongenomic pathway, stimulating actin-based endocytosis at the synapse and internalization of D2 from the cell surface to the perinuclear space (8).

Paul J. Davis and his colleagues have made a significant step in understanding the mechanism of nongenomic actions of thyroid hormone in their demonstration of thyroid hormone induction of mitogen-activated protein kinase in HeLa and CV-1 cells [see the current article in focus by Lin et al. (Ref. 9, p. C1014 in this issue)]. That laboratory previously made the observation that thyroid hormone potentiates both the antiviral (11) and immunomodulatory actions (10) of interferon-gamma through a mechanism that is dependent on protein kinase A and protein kinase C. This study by Davis and colleagues delineates this mechanism in detail by demonstrating that T4 directs phosphorylation of STAT1alpha at serine-727 and enhances interferon-gamma activity. They showed a similar level of induction with agarose-bound T4 (which cannot penetrate the cell membrane), indicating that the effector of the thyroid hormone signal must reside in the membrane. The concentration of T4 required to induce these effects, 10-7 M, is two to three orders of magnitude greater than the concentration of T3 added to cell culture media for nuclear effects, although measurement of free T4 in this system shows a concentration of 10-10 M. The estimation of "physiological" hormone concentrations in an in vitro system is always difficult, but the comparison with concentrations required for nuclear actions has caused some to question the significance of these effects. Another concern has been the study of a "potentiating" effect, thyroid hormone modulation of interferon-gamma , rather than a direct action that has an absolute requirement for thyroid hormone. Although such potentiating effects are likely to be important, they are more subtle and difficult to define mechanistically. For those who remain skeptical, the identification and cloning of the membrane effector(s) will ultimately be required to move forward in the understanding of these effects.

What then is the nature of the membrane receptor that mediates these actions? Davis and colleagues have previously identified membrane binding sites on red blood cell membranes (4) and others have shown sites on vascular smooth muscle cells (12). Interestingly, a recent report has demonstrated the expression of transfected nuclear estrogen receptor alpha - and beta -cDNA in the membrane of Chinese hamster ovary cells, although at 3% of levels in the nucleus (13). This membrane-bound receptor activates Gqalpha and Gsalpha and the enhanced nuclear incorporation of thymidine dependent on activation of mitogen-activated protein kinase, as is shown for thyroid hormone in this study. The ligand affinity for the thyroid hormone membrane receptor, with a preference for T4 over T3, makes it unlikely that nongenomic effects of T4 are mediated by membrane expression of the nuclear receptor, which has a clear preference for T3. Recent success in cloning of the long-sought membrane transporter for thyroid hormone (1), and of the sodium iodide symporter (3), indicates the potential of expression cloning of membrane proteins when the functional characteristics have been well characterized.

What model systems can then be used to test nongenomic actions of thyroid hormone in a physiological context? An important tool in evaluating the function of thyroid hormone nuclear receptors has been TR gene inactivations (6). Although significant abnormalities have been identified in a number of these models, some areas, such as the brain, have had minimal findings (14). Is the milder-than-expected phenotype just compensation from the other TR isoform or an indication that nongenomic actions of thyroid hormone are more significant than previously thought? As mice with combined TR-alpha and -beta deficiency become available for study, they will represent an ideal model to test nongenomic effects of thyroid hormone in a physiological context.

These current results from the Davis laboratory are an important step in defining a mechanism of nongenomic effects of thyroid hormone, especially in showing how a thyroid hormone signal at the membrane can be transduced to modify gene expression. This should provide a framework to test whether these same pathways are utilized in other nongenomic actions of thyroid hormone. The potential for complexity of interacting signal pathways from the membrane is likely to equal or exceed that for nuclear action. Ultimately, successful cloning of the thyroid hormone membrane receptor(s) will significantly increase attention to this important area of thyroid hormone action.


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1.   Abe, T., M. Kakyo, H. Sakagami, T. Tokui, T. Nishio, M. Tanemoto, H. Nomura, S. C. Hebert, S. Matsuno, and H. Kondo. Molecular characterization and tissue distribution of a new organic anion transporter subtype (oatp3) that transports thyroid hormones and taurocholate and comparison with oatp2. J. Biol. Chem. 273: 22395-22401, 1998[Abstract/Free Full Text].

2.   Brent, G. A. The molecular basis of thyroid hormone action. N. Engl. J. Med. 331: 847-853, 1994[Free Full Text].

3.   Dai, G., O. Levy, and N. Carrasco. Cloning and characterization of the thyroid iodide transporter. Nature 379: 458-460, 1996[Medline].

4.   Davis, F. B., V. Cody, P. J. Davis, L. J. Borzynski, and S. D. Blas. Stimulation by thyroid hormone analogues of red blood cell Ca2+-ATPase activity in vitro. Correlations between hormone structure and biological activity in a human cell system. J. Biol. Chem. 258: 12373-12377, 1983[Abstract/Free Full Text].

5.   Davis, P. J., and F. B. Davis. Nongenomic actions of thyroid hormone. Thyroid 6: 497-504, 1996[Medline].

6.   Hsu, J.-H., and G. A. Brent. Thyroid hormone receptor gene knockouts. Trends Endocrinol. Metab. 9: 103-112, 1998.

7.   Lazar, M. A. Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr. Rev. 14: 270-279, 1993.

8.   Leonard, J. L., and A. P. Farwell. Thyroid hormone-regulated actin polymerization in brain. Thyroid 7: 147-151, 1997[Medline].

9.   Lin, H.-Y., F. B. Davis, J. K. Gordinier, L. J. Martino, and P. J. Davis. Thyroid hormone induces activation of mitogen-activated protein kinase in cultured cells. Am. J. Physiol. 276 (Cell Physiol. 45): C1014-C1024, 1999[Abstract/Free Full Text].

10.   Lin, H.-Y., L. J. Martino, B. D. Wilcox, F. B. Davis, J. K. Gordinier, and P. J. Davis. Potentiation by thyroid hormone of human IFN-gamma -induced HLA-DR expression. J. Immunol. 161: 843-849, 1998[Abstract/Free Full Text].

11.   Lin, H.-Y., P. M. Yen, F. B. Davis, and P. J. Davis. Protein synthesis-dependent potentiation by thyroxine of the antiviral activity of interferon-gamma . Am. J. Physiol. 273 (Cell Physiol. 42): C1225-C1232, 1997[Abstract/Free Full Text].

12.   Ojamaa, K., J. D. Klemperer, and I. Klein. Acute effects of thyroid hormone on vascular smooth muscle. Thyroid 6: 505-512, 1996[Medline].

13.   Razandi, M., A. Pedram, G. L. Greene, and E. R. Levin. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells. Mol. Endocrinol. 13: 307-319, 1999[Abstract/Free Full Text].

14.   Sandhofer, C. R., H. L. Schwartz, C. N. Mariash, D. Forrest, and J. H. Oppenheimer. Beta receptor isoforms are not essential for thyroid hormone-dependent reglation of PCP2 and myelin basic protein gene expression in the developing brains of neonatal rats. Mol. Cell. Endocrinol. 137: 109-115, 1998[Medline].


Am J Physiol Cell Physiol 276(5):C1012-C1013
0002-9513/99 $5.00 Copyright © 1999 the American Physiological Society




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