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At least 19 recordsLinked to original sources
PubMed1991

Chromosomal assignment of five cancer-associated rat genes: two thyroid hormone receptor (ERBA) genes, two ERBB genes and the retinoblastoma gene.

Using a panel of somatic cell hybrids that segregate rat chromosomes, the localization of five cancer-related rat genes was determined: (i) two thyroid receptor genes, THRA1/ERBA1 and THRB/ERBA2 on chromosomes 10 and 15 respectively, (ii) two ERBB genes, namely the epidermal growth factor gene (EGFR, also called ERBB1) and the ERBB2 gene (also designated neu) on chromosomes 14 and 10 respectively, and (iii) the retinoblastoma gene, RB1, on chromosome 15. The THRA1/ERBA1 and ERBB2/neu genes are thus included in a synteny group, conserved on rat chromosomes 10 and human chromosome arm 17q.

Alleles↗
PubMed1984

Sequencing the erbA gene of avian erythroblastosis virus reveals a new type of oncogene.

Avian erythroblastosis virus (AEV) contains two distinct oncogenes, erbA and erbB . The erbB oncogene, which is homologous to a portion of the epidermal growth factor receptor, is related to the src family of oncogenes and efficiently transforms erythroblasts, whereas erbA potentiates the effects of erbB by blocking the differentiation of erythroblasts at an immature stage. This "potentiator" was sequenced; the amino acid sequence deduced from it was clearly different from the sequences of other known oncogene products and was related to carbonic anhydrases. These enzymes participate in the transport of carbon dioxide by erythrocytes, the precursors of which are main targets of avian erythroblastosis virus. A src-related oncogene such as erbB in synergy with an activated specific cell-derived gene such as erbA can profoundly affect early erythroid differentiation.

Alpharetrovirus↗
PubMed1993

Rana catesbeiana tadpole red blood cells express an alpha, but not a beta, c-erbA gene.

Thyroid hormone (TH) receptor number in red blood cells (RBCs) from Rana catesbeiana (RC) tadpoles increases 4-fold during both spontaneous and TH-induced metamorphosis, an effect that we have previously shown to be preceded by an increase in the level of c-erbA-related mRNA. The goals of the present study were to obtain an RC c-erbA alpha cDNA that contains the entire open reading frame for a putative TH receptor protein, to determine if this protein has characteristics typical of a TH receptor, and to assess its contribution to the developmentally related increase in TH receptor number. To accomplish this, the missing 5'-sequence of a previously isolated partial RC c-erbA alpha cDNA (RC12) was synthesized by polymerase chain reaction (PCR) and spliced to RC12 to yield a 1490-basepair cDNA (RC15) that contained the entire coding sequence of the receptor protein. Transcription of RC15 followed by translation of its mRNA in a rabbit reticulolysate system yielded a 50-kilodalton protein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The protein binds T3 with high affinity (Kd, approximately 0.1 nM), and its affinity for T3 is at least 5 times that for T4. The results of cotransfection studies indicate that RC15 can function as a TH receptor; when COS cells were cotransfected with a construct consisting of RC15 cloned in the expression vector CMV4 and TK28 mult, a construct containing rat GH gene TH response element sequences up-stream of a chloramphenicol acetyltransferase reporter gene, chloramphenicol acetyltransferase activity is expressed in the presence, but not in the absence, of T3. To determine whether RBCs contain any c-erbA beta mRNA transcripts that might contribute to the developmentally related increase in the transcripts detected using RC c-erbA alpha cDNAs, alpha- and beta-specific cDNAs were synthesized by PCR and used as probes in a variety of hybridization assays. In all experiments using conditions in which c-erbA beta transcripts were detectable in other tissues, there was no evidence that tadpole RBCs contained such species. Lack of any beta-specific transcripts was confirmed by PCR, using as template cDNA prepared by reverse transcription of RC RBC RNA. It was also noted that the RBC at metamorphic climax is the tissue with the highest content of alpha-specific c-erbA transcripts. It is concluded that the c-erbA alpha gene encodes a TH receptor, and that only the alpha-gene is expressed in tadpole RBCs and subject to regulation during development and by TH.

Amino Acid Sequence↗
PubMed1991

Independent expression of the alpha and beta c-erbA genes in developing rat brain.

Thyroid hormone is important for normal brain development. Cellular responses to thyroid hormone are mediated by multiple nuclear receptors, classified into alpha- and beta-subtypes. In the rat, expression of both the alpha and beta genes results in several translation products. By using cRNA probes common to alpha transcripts or specific for alpha-1 and beta-1, we have studied the distribution of these transcripts in rat brain at different stages of development from embryonic day 14 to adult age by using in situ hybridization histochemistry. On embryonic day 14, the alpha-1 mRNA is already widely expressed at a low level in the developing brain. The alpha-1 mRNA is developmentally regulated and showed a peak in expression during the first 3 postnatal weeks in the cerebral cortex, amygdala, hippocampus, and cerebellum. The probe common to the alpha transcripts detected a widespread distribution and high levels of these forms in the same regions throughout postnatal development. The level of beta-1 mRNA before birth was low or undetectable. The beta-1 transcript showed developmental regulation as well, with a high level at birth in the mitral cell layer of the olfactory bulb, accumbens nucleus, caudate, and hippocampal field CA1 and increasing levels in other regions later during development. Complementary expression of the alpha and beta forms was seen in the cerebral cortex and hippocampus. The differential temporal and spatial distribution as well as coexpression at comparable levels in certain brain regions suggest different roles for the c-erbA proteins during brain development and in the mature animal.

Age Factors↗
PubMed1988

Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c-erbA beta gene.

Multiple cDNAs belonging to the c-erbA gene family encode proteins that bind T3 with high affinity. However, the biological functions of these multiple thyroid hormone receptors have not yet been clarified. Generalized thyroid hormone resistance (GTHR) refers to a human syndrome characterized by tissue refractoriness to the action of thyroid hormones; several studies have suggested quantitative or qualitative defects in T3 binding to nuclear receptors in certain kindreds. To investigate the biological functions of the c-erbA genes, c-erbA alpha and c-erbA beta, we tested the hypothesis that an abnormal c-erbA gene product is present in GTHR by examining these genes in members of one kindred. Restriction enzyme analysis failed to identify an abnormal pattern in affected individuals suggesting no rearrangements or large deletions. However, we demonstrated that the gene conferring the GTHR phenotype is tightly linked to the c-erbA beta locus on chromosome 3. This linkage strongly suggests that the c-erbA beta gene is important in man as a thyroid hormone receptor and identifies a putative c-erbA beta mutant phenotype with central nervous system, pituitary, liver, metabolic, and growth abnormalities.

Drug Resistance↗
PubMed1989

Presence of two members of c-erbA receptor gene family (c-erbA beta and c-erbA2) in smallest region of somatic homozygosity on chromosome 3p21-p25 in human breast carcinoma.

The loss of heterozygosity of genes on the short arm of chromosome 3 (3p) in human breast carcinomas occurs in a region involved in other malignancies, including renal cell carcinoma, lung cancers, and von Hippel-Lindau disease. This finding suggests the presence of a gene(s) that plays a crucial role in multiple cancers. In our study of 84 informative (heterozygous) primary breast tumors, 30% showed losses of heterozygosity on chromosome 3. The shortest region of homozygosity in primary human breast tumor is located between the DNF15S2 and RAF1 loci in the 3p21-p25 region on the short arm of chromosome 3. This region includes at least two members of the c-erbA steroid/thyroid hormone receptor family (c-erbA beta and c-erbA2) that may be of special relevance to breast cancer. Furthermore, tumors with a loss of heterozygosity of genes on chromosome 3 were previously reported to have frequent allelic deletions on chromosome 11p and amplification of the c-myc proto-oncogene. These results highlight the occurrence of multiple genetic alterations in breast tumors.

Breast Neoplasms↗
PubMed1991

The thyroid hormone receptor gene (c-erbA alpha) is expressed in advance of thyroid gland maturation during the early embryonic development of Xenopus laevis.

The c-erbA proto-oncogene encodes the thyroid hormone receptor, a ligand-dependent transcription factor which plays an important role in vertebrate growth and development. To define the role of the thyroid hormone receptor in developmental processes, we have begun studying c-erbA gene expression during the ontogeny of Xenopus laevis, an organism in which thyroid hormone has well-documented effects on morphogenesis. Using polymerase chain reactions (PCR) as a sensitive assay of specific gene expression, we found that polyadenylated erbA alpha RNA is present in Xenopus cells at early developmental stages, including the fertilized egg, blastula, gastrula, and neurula. By performing erbA alpha-specific PCR on reverse-transcribed RNAs from high-density sucrose gradient fractions prepared from early-stage embryos, we have demonstrated that these erbA transcripts are recruited to polysomes. Therefore, erbA is expressed in Xenopus development prior to the appearance of the thyroid gland anlage in tailbud-stage embryos. This implies that erbA alpha/thyroid hormone receptors may play ligand-independent roles during the early development of X. laevis. Quantitative PCR revealed a greater than 25-fold range in the steady-state levels of polyadenylated erbA alpha RNA across early stages of development, as expressed relative to equimolar amounts of total embryonic RNA. Substantial increases in the levels of erbA alpha RNA were noted at stages well after the onset of zygotic transcription at the mid-blastula transition, with accumulation of erbA alpha transcripts reaching a relative maximum in advance of metamorphosis. We also show that erbA alpha RNAs are expressed unequally across Xenopus neural tube embryos. This differential expression continues through later stages of development, including metamorphosis. This finding suggests that erbA alpha/thyroid hormone receptors may play roles in tissue-specific processes across all of Xenopus development.

Animals↗
PubMed1993

Molecular cloning and characterization of the promoter region of the human c-erbA alpha gene.

The c-erbA alpha gene encodes the alpha type thyroid hormone receptor. This gene is expressed in various types of cells, its expression being relatively high in the central nervous system. A genomic clone that contains the 5'-terminal portion of the human c-erbA alpha gene was isolated. The 615 base pair (bp) 5'-flanking sequence of the c-erbA alpha gene showed promoter activity when placed upstream of the bacterial chloramphenicol acetyltransferase gene and transfected into HeLa cells. Nine transcriptional initiation sites were detected within this sequence by S1 nuclease protection analysis. DNA sequence analysis showed that the promoter region contains ten putative binding sites for transcriptional factor Sp1 in the GC rich region (86%). Three putative cAMP responsive elements (CRE) and one putative TPA responsive element (TRE) were identified upstream of the GC rich region. The c-erbA alpha promoter sequence also contains a putative binding site for the Krox-20 transcriptional factor, which is thought to play a role in early development of the mouse central nervous system.

Base Sequence↗
PubMed1994

Cloning of a thyroid hormone-responsive Rana catesbeiana c-erbA-beta gene.

Two types of thyroid hormone receptor (c-erbA) gene have been identified in mammals and in lower species including chickens and the amphibian Xenopus laevis. The two genes are located on different chromosomes and have been named TR alpha and TR beta. We have described previously the cloning of a TR alpha cDNA from Rana catesbeiana (RC) tissues (RC15) and we now report the cloning of a TR beta cDNA from this species. The cloning strategy employed utilized the polymerase chain reaction (PCR), with primers based on the sequences of the X. laevis TR beta cDNA (XenTR beta) and an RCTR beta genomic clone, which, by analogy with XenTR beta, contains some of the 3' end of the open reading frame together with 3'-untranslated sequences. At the nucleotide and amino acid levels, respectively, the cloned RCTR beta cDNA is 90% and 98% homologous with XenTR beta, and 72% and 76% homologous with RC15. Following in vitro transcription and translation, the cDNA was shown to encode a 48 kilodalton protein which binds 3,5,3'-triiodothyronine (T3) with high affinity (mean Kd: 0.032 nM). Samples of total or poly(A) +RNA from tadpoles at different stages of metamorphosis and from adult frogs were analyzed for the presence of TR beta-specific transcripts by slot blot analysis using as probe a 258 bp section of the RCTR beta cDNA. This section of the cDNA does not hybridize to the corresponding section of RC15. In confirmation of previous findings, beta-specific transcripts were not detected in RNA from tadpole red blood cells (RBCs) and none was found in RBCs from adult frogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1991

v-erbA overexpression is required to extinguish c-erbA function in erythroid cell differentiation and regulation of the erbA target gene CAII.

The v-erbA oncoprotein represents a retrovirus-transduced oncogenic version of the thyroid hormone (T3/T4) receptor c-erbA (type alpha). It contributes to virus-induced erythroleukemia by efficiently arresting differentiation of red cell progenitors and by suppressing transcription of erythrocyte-specific genes. Here, we show that v-erbA and c-erbA bind directly to sequences within the promoter of the erythrocyte-specific carbonic anhydrase II (CAII), a gene whose transcription is efficiently suppressed by v-erbA. This erbA-binding site confers thyroid hormone responsiveness to a heterologous promoter in transient expression experiments and is a target for efficient down-regulation of CAII transcription by the v-erbA oncoprotein. In stably transformed erythroblasts coexpressing the v-erbA oncoprotein and the c-erbA/T3 receptor at an approximately equimolar ratio, c-erbA activity is dominant over v-erbA. T3 efficiently induced erythroid differentiation in these cells, thus overcoming the v-erbA-mediated differentiation arrest. Likewise, T3 activated CAII transcription as well as transient expression of a T3-responsive reporter gene containing the CAII-specific erbA-binding site. The c-erbA-dependent activation of this CAII reporter construct could only be suppressed by very high amounts of v-erbA. Our results suggest that overexpression of v-erbA is required for its function as an oncoprotein.

Base Sequence↗
PubMed1993

Close proximity of c-erbA2 and c-erbA-beta genes on the short arm of chromosome 3.

The common loss region on the short arm of chromosome 3 (3p) in human breast tumors harbors two members of the c-erbA receptor gene family, c-erbA2 and c-erbA-beta, both of which recognize a BamHI polymorphism in human genomic DNA. Analysis of lymphocyte DNAs from 50 normal individuals and lymphocyte DNAs from 50 normal individuals and lymphocyte and tumor DNAs from 116 breast cancer patients revealed identical genotypes (a/a, b/b or a/b) for both probes. Furthermore, deletion of the same allele (a/- or -/b) of c-erbA2 and c-erbA-beta was detected in 25% of the 66 breast tumors from patients with constitutionally heterozygous genotypes for both genes. No sequence homology was detected between the c-erbA2 and c-erbA-beta genes, suggesting a physical linkage between these two genes. Digestion of the genomic DNA with combinations of restriction enzymes and hybridization with c-erbA2, which is a genomic fragment, and c-erbA-beta, which is a cDNA clone, provide evidence that c-erbA2 and a region of the c-erbA-beta gene are physically contiguous on the short arm of chromosome 3 and are separated by no more than 1.8 kb of DNA sequences.

Breast Neoplasms↗
PubMed1991

Genomic organization of the human thyroid hormone receptor alpha (c-erbA-1) gene.

The thyroid hormone receptor alpha (THRA or c-erbA-1) gene belongs to a family of genes which encode nuclear receptors for various hydrophobic ligands such as steroids, vitamin D, retinoic acid and thyroid hormones. These receptors are composed of several domains important for hormone-binding, DNA-binding, dimerization and activation of transcription. We show here that the human THRA gene is organized in 10 exons distributed along 27 kbp of genomic DNA on chromosome 17. The position of the introns in human THRA is highly conserved when compared to the chicken gene despite their differing lengths. The N-terminal A/B domain as well as the 5' untranslated region is encoded by two exons. Interestingly, each of the putative zinc fingers of the receptor DNA-binding domain is encoded by one exon and the hormone-binding domain is assembled from three exons. The two last exons of the gene are alternatively spliced to generate two different messenger RNAs. In addition, we confirm that another gene, belonging to the nuclear receptor superfamily, ear-1, overlaps with the 3' region of THRA in an opposite transcriptional orientation.

Amino Acid Sequence↗
PubMed1993

Characterization of a functional promoter for the human thyroid hormone receptor alpha (c-erbA-1) gene.

The thyroid hormone receptor alpha (THRA or c-erbA-1) gene belongs to a family of genes that encode nuclear receptors for various hydrophobic ligands such as steroids, retinoic acid and thyroid hormones. We have previously described the genomic organization of the human THRA gene, which comprises 10 exons distributed along 27 kbp of genomic DNA. We describe here a promoter that initiates THRA transcription. This promoter contains no obvious TATA-like element but is very GC rich and harbors numerous Sp1 sites. It also contains several sites similar to previously described cis-acting sequences including hormone-responsive elements (HREs). When transfected into cultured HeLa cells, it drives the expression of a CAT reporter gene. The activity of this human THRA promoter is enhanced by the synthetic glucocorticoid dexamethasone but seems unaffected by thyroid hormones.

Animals↗
PubMed1991

Tight linkage of the human c-erbA beta gene with the syndrome of generalized thyroid hormone resistance is present in multiple kindreds.

Generalized thyroid hormone resistance recently was reported to map in a single kindred to the same chromosomal region as the c-erbA beta gene, which codes for a putative thyroid hormone receptor. Restriction fragment length polymorphisms (RFLPs) of c-erbA beta were linked with GTHR in three kindreds with variable neuropsychologic dysfunction; two unrelated kindreds have been reported to possess different single base mutations in the T3 binding domain of c-erbA beta. In order to ascertain if tight linkage with c-erbA beta could be generalized to other families with this syndrome, we performed RFLP analysis in a separate laboratory on an unrelated family with GTHR which lacks the neuropsychologic defects or short stature often associated with GTHR (Kindred WR). RFLPs were identified after Bam Hl and Eco RV digestion of DNA from leukocytes from 14 family members. The Bam Hl RFLPs were 2.8 and 5.3 kb bands, and the Eco RV RFLPs were 1.6 and 3.3 kb bands. These RFLPs cosegregated with the GTHR phenotype and 11 family members were informative when both RFLPs were employed. The logarithm of the odds ratio between GTHR and c-erbA beta was 3.67, and therefore GTHR mapped to the c-erbA beta locus in this kindred. Allelic-specific hybridization with a probe constructed to identify the C to A mutation at nucleotide position 1643 (previously identified in one other kindred) suggested that our family has a different c-erbA beta abnormality. Although GTHR appears to be commonly associated with alterations in the human c-erbA beta gene, different kindreds may inherit different genetic defects.

Base Sequence↗
PubMed1983

Isolation and characterization of multiple human genes homologous to the oncogenes of avian erythroblastosis virus.

Human DNA sequences complementary to the oncogenes v-erbA and v-erbB of avian erythroblastosis virus have been isolated from a genomic DNA library. Two clones, lambda he-A1 and lambda he-A2, were related to the erbA gene and one to the erbB gene (lambda he-B). The two erbA genes were only distantly related to each other as judged from hybridization analysis. Furthermore, human chromosomal DNA appears to contain one or two additional genes analogous to the lambda he-A2 sequence, whereas the mouse genome contained only two genes complementary to lambda he-A1 and lambda he-A2, respectively. Polyadenylated RNA species, 5.0 kb in size, were found in the human HeLa and the human hematopoietic K562 cell lines, suggesting that at least some of the erb-related genes are active and do not represent pseudogenes. Taken together, the data demonstrate that two distantly related classes of erbA genes exist in human and mouse DNA, and that multiple copies of genes belonging to one of these two classes exist in the human genome.

Alpharetrovirus↗
PubMed1985

The four C-terminal amino acids of the v-erbA polypeptide are encoded by an intronic sequence of the v-erbB oncogene.

The genome of avian erythroblastosis virus (AEV), a defective acute leukemia retrovirus, carries two distinct cell-derived oncogenes in the structure 5' delta gag-erbA-erbB-delta env3'. The nucleotide sequence of the v-erbA gene was recently reported. In order to determine the boundary between the two adjacent oncogenes, the sequence of the v-erbA/v-erbB junction of AEV was compared to that of a recombinant lambda phage containing a chicken cellular sequence representing the 5' part of c-erbB. The four C-terminal amino acids of v-erbA are in fact encoded by a c-erbB intron-derived sequence thus demonstrating that the virus acquired a truncated c-erbA gene. Furthermore the 7 to 10 amino acid residues upstream from the 4 C-terminal amino acids mentioned above appeared to be derived from env-related sequences. The splice acceptor site at the beginning of the only open reading frame for v-erbB is also present and functional in c-erbB when expressed to generate a truncated EGF (epidermal growth factor) receptor. Thus AEV joins a truncated erbA gene to a truncated erbB gene through env-derived sequences and intronic sequences from c-erbB.

Alpharetrovirus↗