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Sheau Yu Teddy Hsu

Publications and source records attributed to Sheau Yu Teddy Hsu.

12 recordsLinked to original sources
PubMed2006

Intermedin: a skin peptide that is downregulated in atopic dermatitis.

Intermedin (IMD), also called adrenomedullin-2, is a peptide that belongs to the calcitonin/calcitonin gene-related peptide/amylin peptide family. IMD exerts many effects on the cardiovascular system, gastrointestinal tract, and central nervous system. Here, we analyzed the expression of the IMD peptide in human skin of healthy controls, in biopsies from lesional and non-lesional areas of atopic dermatitis (AD) skin, in cultured human keratinocytes, and in the HaCaT keratinocyte cell line at the transcriptional (quantitative reverse transcription-PCR) and translational (immunohistochemistry) level. IMD messenger RNA (mRNA) and protein could be detected in keratinocytes and human skin. Keratinocytes, nerve fibers, periglandular cells, arterial/arteriolar smooth muscle cells, and pericytes of dermal microvessels were intensely IMD-immunoreactive. The IMD mRNA was, compared to healthy skin, significantly reduced in lesional and non-lesional areas of AD skin. This was accompanied by a reduction of IMD immunoreactivity in pericytes of the upper dermis indicating that skin from AD patients is generally affected, and downregulation of IMD in AD skin is not a secondary phenomenon caused by acute inflammation but is a general characteristic of AD skin. These data further point to a role of IMD expressed by pericytes in conferring higher susceptibility of the skin of AD patients to inflammatory stimuli.

Adult↗
PubMed2005

Intermedin functions as a pituitary paracrine factor regulating prolactin release.

Calcitonin, alpha- and beta-calcitonin gene-related peptides, amylin, and adrenomedullin belong to a unique group of peptide hormones important for homeostasis maintenance. We recently identified intermedin (IMD) as a novel member of the calcitonin/calcitonin gene-related peptide family expressed in the pituitary, digestive tract, and other organs of vertebrates. Real-time PCR and immunohistochemical analysis of pituitaries from rats at different stages of development showed that IMD is expressed in the intermediate lobe and select adrenocorticotrophs in the anterior lobe, suggesting that IMD could function as a paracrine factor regulating anterior pituitary hormone secretion. In support of a paracrine role for IMD in the pituitary, quantitative and in situ hybridization analyses showed the expression of IMD receptor transcripts including the calcitonin receptor-like receptor and receptor activity-modifying proteins in the pituitary. Treatment with IMD leads to a dose-dependent increase of prolactin release in cultured rat pituitary cells. In contrast, IMD treatment has negligible effects on the release of GH, FSH, or ACTH. Likewise, in vivo treatment with IMD leads to an elevation of plasma prolactin levels in conscious rats. Based on these functional characteristics, we hypothesized that IMD could represent one of the intermediate lobe-derived prolactin-releasing factors important for prolactin regulation during reproduction. In support of this hypothesis, studies of IMD expression in lactating and ovariectomized rats showed that pituitary IMD transcripts in lactating animals increased to more than 2-fold over nonlactating controls whereas ovariectomy leads to a 90% reduction of IMD expression in the pituitary. Of importance, subsequent treatment with 17beta-estradiol or diethylstilbestrol increased pituitary IMD expression in ovariectomized rats. In addition, analysis of the proximate region of the IMD gene promoter showed that the IMD gene promoter contains consensus estrogen response element sequences, and estrogen treatments up-regulate the promoter reporter activity in transfected pituitary cells. Collectively, the present study indicates that IMD represents a novel estrogen-dependent intermediate lobe-derived prolactin-releasing factor and could play important roles in the regulation of prolactin release during reproduction in females.

Adrenocorticotropic Hormone↗
PubMed2005

Relaxin research in the postgenomic era.

Because of the coevolution of ligands and their cognate receptors, analysis of human genomic sequences allows prediction of the pairing of these elements. Initially, we identified a group of five human leucine-rich repeat-containing G-protein-coupled receptor (LGR) genes homologous to LH, FSH, and TSH receptors. Based on common phenotypes of INSL3 null mice and transgenic mice with LGR8 gene deletion, we hypothesized that INSL3, relaxin, and related genes are likely ligands for the paralogous LGR7 and LGR8 genes. Matching the relaxin family peptides with these two orphan LGRs led to the finding that relaxin is capable of activating LGR7 and LGR8 through the Gs pathway. In addition, INSL3 and relaxin 3 were found to be specific ligands for LGR8 and LGR7, respectively. Based on the known production of INLS3 by testicular Leydig cells and ovarian theca cells, we demonstrated the expression of the INSL3 receptor LGR8 in oocytes in ovary and in male germ cells in the testis. Furthermore, we found that LH stimulates INSL3 transcripts in ovarian theca and testicular Leydig cells. INSL3, in turn, binds LGR8 expressed in germ cells to initiate the meiotic progression of arrested oocytes in preovulatory follicles in vitro and in vivo and to suppress male germ cell apoptosis in vivo. INSL3 interacts with germ cells to activate the inhibitory G protein, thus leading to decreases in cAMP production. Our data demonstrate the importance of the INSL3-LGR8 paracrine system in mediating gonadotropic actions in both ovary and testis.

Animals↗
PubMed2005

Evolution of the signaling system in relaxin-family peptides.

Recent studies have characterized two G-protein-coupled receptors (GPCRs), LGR7 and LGR8, as relaxin receptors. Later studies have shown that LGR7 and LGR8 also are cognate receptors for the relaxin-family peptides, INSL7/relaxin3 and INSL3, respectively. In addition, INSL7/relaxin3 signals through two orphan GPCRs, GPCR135 and GPCR142, whereas INSL5 is a select ligand for GPCR142. These findings have greatly enhanced our understanding of the physiology and signaling of this unique group of peptide hormones. Phylogenetic analysis of relaxin-family peptides and their co-evolved receptors suggests that the ancestor relaxin gene duplicated multiple times in a vertebrate branch-specific manner. Among the seven human relaxin-family peptides (relaxin1, relaxin2, INSL3/RLF, INSL4/EPIL, INSL5/RIF2, INSL6/RIF1, and INSL7/relaxin3), INSL7 and INSL5 could represent the most ancient form. By contrast, the most widely studied family peptides, human relaxins H1 and H2, appear to be derived from recent gene duplication in mammals. Therefore, relaxin-family peptides could be important for the evolution and adaptation to lineage-specific physiologic processes during evolution. Duplicated relaxin-family genes assumed regulatory roles in newly evolved reproductive processes, and relaxin/LGR signaling was harnessed for signaling in the uterus and mammary gland in addition to other tissues. Although the precise evolutionary history of relaxin ligand/receptor pairs remains to be elucidated, these findings indicate that the expansion of relaxin-family genes and their specific regulatory functions have evolved during vertebrate evolution to allow the development of a tissue-specific regulatory mechanism in a lineage-specific manner and provide a revealing portrait of molecular evolution in action.

Animals↗
PubMed2005

Conservation of the heterodimeric glycoprotein hormone subunit family proteins and the LGR signaling system from nematodes to humans.

Glycoprotein hormones, follicle-stimulating hormones (FSHs), luteinizing hormones (LHs), thyroid-stimulating hormones (TSHs), and chorionic gonadotropin (CG) are key endocrine hormones secreted from the pituitary gonadotrophs and thyrotrophs and the placenta in primates. These hormones, consisting of a common alpha subunit and a specific beta subunit, act through the FSH receptor (FSHR), the LH receptor (LHR), and the TSH receptor (TSHR) that are highly specific for their cognate hormones. These glycoprotein hormones are structurally and functionally conserved in various vertebrates and have been identified in most lineages of actinopterygians (bony fish) and sarcopterygians (tetra-pods). Of interest, recent genomic studies showed that vertebrate glycoprotein hormone receptors belong to an ancient subfamily of G protein-coupled receptors (GPCRs) named as leucine-rich repeat-containing GPCRs (LGRs). These findings have prompted the hypothesis that there could be additional glycoprotein hormones in vertebrate genomes. Indeed, searches of vertebrate genomes have led to the identification of two novel glycoprotein hormone subunits, glycoprotein alpha 2 (GPA2) and glycoprotein beta 5 (GPB5), as well as their homologs in invertebrates. Subsequently, it was demonstrated that GPA2 and GPB5 form a heterodimeric hormone, thyrostimulin/OGH, capable of activating TSHR in vivoand the thyroid axis in transgenic mice. However, the exact role of this novel glycoprotein hormone and its homolog in invertebrates is not clear. To gain a better understanding of the physiological role of the novel glycoprotein hormone subunits and their evolution, it is imperative to carry out systematic studies of these genes in representative model species. In the present report, we summarize our findings based on studies of genomes of model organisms from sea anemones to humans. We found that GPA2 and GPB5 represent the ancient forms of glycoprotein hormone alpha and beta subunits, respectively, and that vertebrate and invertebrate glycoprotein hormone subunit proteins shared common ancestors that evolved during early metazoan evolution. It is important to note that glycoprotein hormone alpha and beta subunit proteins from invertebrates formed a heterodimer with structural functional characteristics similar to that of vertebrate glycoprotein hormones. Taken together, both glycoprotein hormone alpha and beta subunits evolved before the evolution of nematodes, arthropods, and vertebrates.

Amino Acid Sequence↗
PubMed2004

Bioinformatics in reproductive biology--functional annotation based on comparative sequence analysis.

Recent studies of the genomes of a variety of model organisms have provided an unprecedented opportunity to identify and characterize all signaling molecules in the human genome. Regardless of the approaches used to decipher gene characteristics and their role in physiology, pairwise sequence comparison represents the fundamental bioinformatic tool for initial functional annotation of newly identified genes. Because genes evolved from duplication and adapted to different evolutionary niches for each organism during speciation, detailed sequence analysis could provide additional information on the biochemical and biological characteristics of novel genes. In addition, the integration of sequence-based gene discovery with phylogeny-based function prediction leads to a more complete understanding of the signaling pathways. For example, detailed pairwise sequence analysis has led to the identification of (1) stresscopin (SCP) and stresscopin-related peptides (SRP) as the CRH-related genes, (2) multiple relaxin-like factor genes, and (3) the novel glycoprotein hormone subunit family genes, alpha2 and beta5. Furthermore, based on the understanding that ligands and receptors coevolved during evolution, we have identified a variety of novel extracellular signaling polypeptides including (1) stresscopin and stresscopin-related peptides as selective ligands for the type 2 CRH receptor, (2) the pregnancy hormone, relaxin, and related peptides that activate two orphan G protein-coupled receptors (GPCRs), LGR7 and LGR8, and (3) alpha2 and beta5 that form a heterodimer capable of activating the TSH receptor. Thus, detailed studies on the characteristics and evolution of gene sequences have provided an inroad to the elucidation of novel signaling polypeptides and the associated signal transduction pathways.

Animals↗
PubMed2004

Intermedin, a novel calcitonin family peptide that exists in teleosts as well as in mammals: a comparison with other calcitonin/intermedin family peptides in vertebrates.

Endocrine regulation in vertebrates is critical for the adaptation and regulation of homeostasis. The G protein-coupled receptor (GPCR) signaling transduction system represents one of the most ancient forms of cell surface signaling. Recently, comparative sequence analysis has aided in the identification and pairing of a variety of ligand/GPCR signaling systems. Among the ligands of type II GPCRs, the calcitonin family peptides including calcitonin, alpha-calcitonin gene-related peptide (alphaCGRP), betaCGRP, adrenomedullin, and amylin are among the best studied hormones, and the founding member, calcitonin, was originally identified and isolated from teleosts. This unique group of peptides shares a conserved tertiary structure with an N-terminal disulfide-bridged ring. In mammals, these peptides signal through two closely related type II GPCRs and three unique receptor activity-modifying proteins. Recently, based on the analysis of multiple vertebrate genomes, we identified a novel calcitonin/CGRP family peptide named intermedin. Here we show that in humans the five paralogous family genes, calcitonin, CGRP, amylin, adrenomedullin, and intermedin, evolved before the emergence of modern vertebrates, and that teleost genomes carry multiple copies of these co-evolved hormone genes. Sequence comparison showed that each of these genes is highly conserved in different vertebrates and that multiple copies of these peptides in teleosts could be derived from ancient genome duplication and/or lineage-specific intragenic duplications. The present article provides an overview of the calcitonin/intermedin family peptides found in teleost and mammalian genomes, and describes their putative functions. In addition, we demonstrate that one of the intermedin orthologs deduced from the pufferfish (Fugu rubripes) genome shares a conserved signaling activity with mammalian intermedin. The combined results indicate that the physiology associated with each of these family peptides likely evolved during early vertebrate evolution and diverged to serve select physiological functions in different vertebrates.

Adrenomedullin↗
PubMed2004

Ancient evolution of stress-regulating peptides in vertebrates.

Recent studies on genomic sequences have led to the discovery of novel corticotropin-releasing factor (CRF) type 2 receptor-selective agonists, stresscopin (SCP)/urocortin III (UcnIII), and stresscopin-related peptide (SRP)/urocortin II (UcnII). In addition, analyses of vertebrate genomes showed that the CRF peptide family includes four distinct genes, CRF, urocortin/urotensin I, SCP/UcnIII, and SRP/UcnII. Each of these four genes is highly conserved during evolution and the identity between mammalian and teleost orthologs ranges from >96% for CRF to >55% for SCP. Phylogenetic studies showed that the origin of each of these peptides predates the evolution of tetrapods and teleosts, and that this family of peptide hormones evolved from an ancestor gene that developed the CRF/urocortin and SCP/SRP branches through an early gene duplication event. These two ancestral branches then gave rise to additional paralogs through a second round of gene duplication. Consequently, each of these peptides participates in the regulation of stress responses over the 550 million years of vertebrate evolution. The study also suggested that the fight-or-flight and stress-coping responses mediated mainly by CRF types 1 and 2 receptors evolved early in chordate evolution. In addition, we hypothesize that the CRF/CRF receptor signaling evolved from the same ancestors that also gave rise to the diuretic hormone/diuretic hormone receptors in insects. Thus, a complete inventory of CRF family ligands and their receptors in the genomes of different organisms provides an opportunity to reveal an integrated view of the physiology and pathophysiology of the CRF/SCP family peptides, and offers new insights into the evolution of stress regulation in vertebrates.

Amino Acid Sequence↗
PubMed2003

Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes.

Calcitonin, calcitonin gene-related peptide (CGRP), adrenomedullin (ADM), and amylin belong to a unique group of peptide hormones important for homeostasis in diverse tissues. Calcitonin is essential for calcium balance, whereas CGRP and ADM are important for neurotransmission and cardiovascular and respiratory regulation. Based on phylogenetic analysis, we identified intermedin as a novel member of the calcitonin/CGRP peptide family. Analysis of intermedin expression indicated that intermedin is expressed primarily in the pituitary and gastrointestinal tract. Intermedin increased cAMP production in SK-N-MC and L6 cells expressing endogenous CGRP receptors and competed with labeled CGRP for binding to its receptors in these cells. In addition, treatment of 293T cells expressing recombinant calcitonin receptor-like receptor (CRLR) and one of the three receptor activity-modifying proteins (RAMPs) showed that a CRLR/RAMP receptor complex is required for intermedin signaling. In contrast to CGRP and ADM, which exhibited a preferential stimulation of CRLR when co-expressed with RAMP1 and RAMP2 or RAMP3, respectively, intermedin represents a nonselective agonist for the RAMP coreceptors. In vivo studies demonstrated that intermedin treatment led to blood pressure reduction in both normal and spontaneously hypertensive rats via interactions with the CRLR/RAMP receptor complexes. Furthermore, in vivo treatment in mice with intermedin led to suppression of gastric emptying activity and food intake. Thus, identification of intermedin as a novel member of the calcitonin/CGRP peptide family capable of signaling through CRLR/RAMP receptor complexes provides an additional player in the regulation of peripheral tissues by CRLR and will allow development of new therapeutic agents for pathologies associated with diverse vascular and gastrointestinal disorders.

Amino Acid Sequence↗
PubMed2003

Relaxin signaling in reproductive tissues.

The insulin/relaxin peptide family includes insulin, IGFs, relaxin1-3, INSL3/RLF, INSL4, INSL5/RIF2 and INSL6/RIF1, many without functional characterization. Based on analysis of transgenic phenotypes and phylogenetic profiling, we have discovered that two orphan leucine-rich repeat-containing G protein-coupled receptors, LGR7 and LGR8, are cognate receptors for relaxin whereas INSL3 is a specific ligand for LGR8. With the identification of the relaxin receptors, it is now possible to investigate specific cells and tissues that are responsive to relaxin in diverse physiological and pathological conditions as well as to develop agonists and antagonists for LGR7 and LGR8 as therapeutics to treat different labor disorders. Furthermore, future functional characterization of the specificity of these pluripoentent receptors with peptide ligands could lead to the understanding of related orphan ligands and receptors.

Animals↗