The c-erb-A gene encodes a thyroid hormone receptor

The cDNA sequence of human c-erb-A, the cellular counterpart of the viral oncogene v-erb-A, indicates that the protein encoded by the gene is related to the steroid hormone receptors. Binding studies with the protein show it to be a receptor for thyroid hormones.     

Identification of a second human retinoic acid receptor

We have previously described a human complementary DNA that encodes a novel protein which is homologous to members of the steroid/thyroid nuclear receptor multigene family. This novel protein (hap for hepatoma) exhibits strong homology with the human retinoic acid receptor (RAR) which has been recently characterized. To test the possibility that the hap protein might also be a retinoid receptor, a chimaeric receptor was created by replacing the putative DNA binding domain of hap with that of the human oestrogen receptor (ER). The resulting hap-ER chimaera was then tested for its ability to trans-activate an oestrogen-responsive reporter gene (vit-tk-CAT) in the presence of possible receptor ligands. Here we show that retinoic acid (RA) at physiological concentrations is effective in inducing the expression of this reporter gene by the hap-ER chimaeric receptor. This demonstrates the existence of two human retinoic acid receptors designated RAR-alpha and RAR-beta.     

Identification of a new class of steroid hormone receptors

The gonads and adrenal glands produce steroids classified into five major groups which include the oestrogens, progestins, androgens, glucocorticoids and mineralocorticoids. Gonadal steroids control the differentiation and growth of the reproductive system, induce and maintain sexual characteristics and modulate reproductive behaviour. Adrenal steroids also influence differentiation as well as being metabolic regulators. The effects of each steroid depend primarily on its specific receptors, the nature of which could therefore provide a basis for classification of steroid hormone action. The successful cloning, sequencing and expression of the human glucocorticoid (hGR) (ref. 1), oestrogen (hER), progesterone (hPR), and mineralocorticoid (hMR) receptors, complementary DNA, plus homologues from various species, provides the first opportunity to study receptor structure and its influence on gene expression. Sequence comparison and mutational analysis show structural features common to all groups of steroid hormone receptors. The receptors share a highly conserved cysteine-rich region which functions as the DNA-binding domain. This common segment allows the genome to be scanned for related gene products: hMR cDNA for example, was isolated using an hGR hybridization probe. In this study, using the DNA-binding domain of the human oestrogen receptor cDNA as a hybridization probe, we have isolated two cDNA clones encoding polypeptides with structural features suggestive of cryptic steroid hormone receptors which could participate in a new hormone response system.     

A novel steroid thyroid hormone receptor-related gene inappropriately expressed in human hepatocellular carcinoma

We have previously isolated from a human hepatocellular carcinoma a hepatitis B virus integration in a 147-base-pair cellular DNA fragment, similar to steroid- and c-erb-A/thyroid-hormone receptor genes. We have now cloned the corresponding complementary DNA from a human-liver cDNA library. Nucleotide sequence analysis revealed that the overall structure of the cellular gene, which we have named hap, is similar to that of the DNA-binding hormone receptors. That is, it displays two highly conserved regions identified as the putative DNA-binding and hormone-binding domains of the c-erb A/steroid receptors. Six out of seven hepatoma and hepatoma-derived cell-lines express a 2.5-kilobase (kb) hap messenger RNA species which is undetectable in normal adult and fetal livers but present in all non-hepatic tissues analysed. The data suggest that the hap gene product may be a novel ligand-responsive regulatory protein whose inappropriate expression in liver may relate to the hepatocellular carcinogenesis.     

A human retinoic acid receptor which belongs to the family of nuclear receptors

A cDNA encoding a protein that binds retinoic acid with high affinity has been cloned. The protein is homologous to the receptors for steroid hormones, thyroid hormones and vitamin D3, and appears to be a retinoic acid-inducible trans-acting enhancer factor, suggesting that the molecular mechanisms of the effect of retinoids (vitamin A) on embryonic development, differentiation and tumour cell growth are similar to those described for other members of this nuclear receptor family.     

Spatial and temporal expression of the retinoic acid receptor in the regenerating amphibian limb

Retinoic acid is known to have dramatic effects on vertebrate limb pattern in development and regeneration, supporting a model in which a gradient of retinoic acid serves as a morphogen to differentially supply positional information to a developing limb. The discovery of a retinoic acid receptor (RAR) and its homology to the steroid and thyroid hormone receptors provided a potential molecular mechanism for limb morphogenesis. One prediction of this model is that the receptor must be expressed in the developing and regenerating limb anlage. We investigated the expression of the RAR in the adult newt, Notophthalmus viridescens, whose amputated limbs are capable of regenerating and upon which retinoic acid can act to alter pattern. We report the cloning of cDNAs encoding a functional newt RAR and the localization of high and uniform levels of RAR mRNA specifically in the regenerating cells that control limb pattern. These results indicate that the morphogenic field is established through differential activation of pre-existing retinoic acid receptors rather than differential expression of the RAR gene.     

A new retinoic acid receptor identified from a hepatocellular carcinoma

Processes as diverse as growth, vision and reproduction depend on the presence of vitamin A and its metabolites (retinoids), but the molecular mechanisms which govern these diverse actions remain unclear (for reviews see refs 1,2). A crucial advance recently was the isolation of a specific nuclear receptor for retinoic acid, one of the physiologically active vitamin A derivatives. This nuclear receptor is a member of the steroid/thyroid hormone receptor family. Our analysis of an uncharacterized member of this class of intracellular receptors, encoded by a complementary DNA clone from a human placental library, has led us to discover a second retinoic acid receptor. This new receptor is expressed at high levels in a number of epithelial-type tissues. The gene for the receptor was first identified in a hepatocellular carcinoma where it surrounds a site of integration of hepatitis B virus. Activation by this virus may play a role in tumour development in liver cells, where it is normally not expressed.     

Complexity of human T-cell antigen receptor beta-chain constant- and variable-region genes

Immune systems of vertebrates function via two types of effector cells, B and T cells, which are capable of antigen-specific recognition. The immunoglobulins, which serve as antigen receptors on B cells, have been well characterized with respect to gene structure, unlike the T-cell receptors. Recently, cDNA clones thought to correspond to the beta-chain locus of the human and mouse T-cell receptor have been described. The presumptive beta-chain clones detect gene rearrangement specifically in T-cell DNA and show homology with immunoglobulin light chains. The similarity of the T-cell beta-chain gene system to the immunoglobulin genes has been further demonstrated by the recent observation of variable- and constant-region gene segments as well as joining segments and putative diversity segments. We report here the characterization of cDNA and genomic clones encoding human T-cell receptor beta-chain genes. There are two constant-region genes (C beta 1 and C beta 2), each capable of rearrangement and expression as RNA. The gene arrangement, analogous to that of mouse beta-chain genes, shows strong evolutionary conservation of the dual C beta gene system in these two species.     

Cloning and expression of a rat D2 dopamine receptor cDNA

Dopamine receptors are classified into D1 and D2 subtypes on the basis of their pharmacological and biochemical characteristics. The D2 dopamine receptor has been implicated in the pathophysiology and treatment of movement disorders, schizophrenia and drug addiction. The D2 dopamine receptor interacts with guanine nucleotide-binding proteins to induce second messenger systems. Other members of the family of receptors that are coupled to G proteins share a significant similarity in primary amino-acid sequence and exhibit an archetypical topology predicted to consist of seven putative transmembrane domains. We have taken advantage of the expected nucleotide sequence similarities among members of this gene family to isolate genes coding for new receptors. Using the hamster beta 2-adrenergic receptor gene as a hybridization probe we have isolated related genes including a cDNA encoding the rat D2 dopamine receptor. This receptor has been characterized on the basis of three criteria: the deduced amino-acid sequence which reveals that it is a member of the family of G-protein-coupled receptors; the tissue distribution of the mRNA which parallels that of the D2 dopamine receptor; and the pharmacological profile of mouse fibroblast cells transfected with the cDNA.