Thyroid hormone receptors (TRs) play a major role in animal physiology.
TRs are important and very interesting regulators of diverse aspects, including
brain development, hearing, bone growth, morphogenesis, metabolism, intestine,
and heart rate in vertebrates (Fig. 1). Aberrant functions of TRs induce
tremendous defects in these pathways. For example, the human disease of
Resistance to Thyroid Hormone (RTH) (see Chapter 8 by Yoh and Privalsky)
is a genetically autosomal dominant inherited syndrome that is caused by mutations
in the gene encoding the TRβ.
Thyroid hormone has various effects on cell proliferation,
growth and apoptosis. To gain more insight into the
molecular dynamics caused by thyroid hormone, gene
expression in HeLaTRcells that constitutively over-expressed the thyroid hormone receptor (TR) was analyzed.
Gene expression profiling of the HeLaTRcells with an
oligonucleotide microarray yielded 229 genes whose
expression was significantly altered by T3.
Thyrotropin-releasing hormone receptor (TRHR) has
already been cloned in mammals where thyrotropin-releas-inghormone (TRH) isknowntoactasapowerful stimulator
of thyroid-stimulating hormone (TSH) secretion. The TRH
receptor of amphibians has not yet been characterized,
although TRH is specifically important in the adaptation of
skin color to environmental changes via the secretion of
a-melanocyte-stimulating hormone (a-MSH).
Activating mutations of the thyroid-stimulating hormone
receptor (TSHr) have been identified as a cause of toxic
adenomas. Germline-inactivating TSHr mutations have
beendescribedas a cause of congenital hypothyroidism. The
effects of combining activating and inactivating mutations
within a single receptor was studied. The double mutant
T477I/P639S contained an activating TSHr mutation
(P639S) togetherwithan inactivatingone (T477I). Theother
one (I486M/P639S) contained two activating mutations.
The thyrotropin receptor (TSHR) undergoes a cleavage at
the cell membrane, leading to a heterodimer, comprising an
aextracellular and a b-transmembrane and intracellular
subunits, held togetherbydisulfidebonds.Moreover, part of
the a-subunit of the receptor is shed from thyroid and
transfected L cells.To understand the role of cleavage and
shedding, we constructed deletion mutants starting,
respectively, at the most N-terminal (S314), and C-terminal
(L378) cleavage sites previously mapped, corresponding to
free b1orb2-subunits without further modification of
Rarely, corticotropin-releasing hormone (CRH) is produced by pancreatic islet tumors, SCLC, medullary thyroid cancer, carcinoids, or prostate cancer. When levels are high enough, CRH can cause pituitary corticotrope hyperplasia and Cushing's syndrome. Tumors that produce CRH sometimes also produce ACTH, raising the possibility of a paracrine mechanism for ACTH production.
A distinct mechanism for ACTH-independent Cushing's syndrome involves ectopic expression of various G protein–coupled receptors in the adrenal nodules.