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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ARTICLE |
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-
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 STAT1
at serine-727 and enhances interferon-
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-
, 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
- and
-cDNA in the membrane of Chinese hamster ovary
cells, although at 3% of levels in the nucleus (13). This
membrane-bound receptor activates Gq
and
Gs
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-
and -
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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Am J Physiol Cell Physiol 276(5):C1012-C1013
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