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Biomedical subjects

B Vennström

Publications and source records attributed to B Vennström.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cardiovascular phenotype and temperature control in mice lacking thyroid hormone receptor-beta or both alpha1 and beta.

We have used a telemetry system to record heart rate, body temperature, electrocardiogram (ECG), and locomotor activity in awake, freely moving mice lacking thyroid hormone receptor (TR)-beta or TR-alpha1 and -beta (TR-alpha1/beta). The TR-alpha1/beta-deficient mice had a reduced heart rate compared with wild-type controls. The TR-beta-deficient mice showed an elevated heart rate, which, however, was unresponsive to thyroid hormone treatment regardless of hormonal serum levels. ECG revealed that the TR-beta-deficient mice had a shortened Q-Tend time in contrast to the TR-alpha1/beta-deficient mice, which exhibited prolonged P-Q and Q-Tend times. Mental or pharmacological stimulation of the sympathetic nervous system resulted in a parallel increase in heart rate in all animals. A single injection of a nonselective beta-adrenergic-receptor blocker resulted in a parallel decrease in all mice. The TR-alpha1/beta-deficient mice also had a 0.4 degrees C lower body temperature than controls, whereas no difference was observed in locomotor activity between the different strains of mice. Our present and previous results support the hypothesis that TR-alpha1 has a major role in determining heart rate under baseline conditions and body temperature and that TR-beta mediates a hormone-induced increase in heart rate.

Adrenergic beta-Antagonists↗
PubMed1999

The adenovirus E1A protein is a potent coactivator for thyroid hormone receptors.

The thyroid hormone receptors interact with several different cofactors when activating transciption. In this study, we show that the adenovirus E1A oncoprotein functions as a strong coactivator for the thyroid hormone receptor (TR), and that TR and E1A synergistically activate transcription via direct (DR4) or palindromic (IRO) hormone-responsive sites. Cotransfection experiments using different isoforms of the chicken TR and E1A show synergistic, ligand-enhanced transactivation. This transactivation is accomplished through a direct, ligand-independent interaction between TR and E1A. The interaction domains in TR are localized to the DNA-binding domain and to the carboxy-terminal part of the ligand-binding domain. In E1A, the regions of interactions are localized to the conserved regions 1 and 3. Both of these domains in E1A are required for a 40-fold enhancement of TR-mediated activation in transfection experiments. Taken together, we show that E1A strongly enhances transcriptional activation, which suggests that it serves as a bridging factor between the receptor and other components of the transcription machinery.

Adenovirus E1A Proteins↗
PubMed1998

Thyroid hormone receptor beta-dependent expression of a potassium conductance in inner hair cells at the onset of hearing.

To elucidate the role of thyroid hormone receptors (TRs) alpha1 and beta in the development of hearing, cochlear functions have been investigated in mice lacking TRalpha1 or TRbeta. TRs are ligand-dependent transcription factors expressed in the developing organ of Corti, and loss of TRbeta is known to impair hearing in mice and in humans. Here, TRalpha1-deficient (TRalpha1(-/-)) mice are shown to display a normal auditory-evoked brainstem response, indicating that only TRbeta, and not TRalpha1, is essential for hearing. Because cochlear morphology was normal in TRbeta-/- mice, we postulated that TRbeta regulates functional rather than morphological development of the cochlea. At the onset of hearing, inner hair cells (IHCs) in wild-type mice express a fast-activating potassium conductance, IK,f, that transforms the immature IHC from a regenerative, spiking pacemaker to a high-frequency signal transmitter. Expression of IK,f was significantly retarded in TRbeta-/- mice, whereas the development of the endocochlear potential and other cochlear functions, including mechanoelectrical transduction in hair cells, progressed normally. TRalpha1(-/-) mice expressed IK,f normally, in accord with their normal auditory-evoked brainstem response. These results establish that the physiological differentiation of IHCs depends on a TRbeta-mediated pathway. When defective, this may contribute to deafness in congenital thyroid diseases.

Aging↗
PubMed1998

Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1.

Thyroid hormone, acting through several nuclear hormone receptors, plays important roles in thermogenesis, lipogenesis and maturation of the neonatal brain. The receptor specificity for mediating these effects is largely unknown, and to determine this we developed mice lacking the thyroid hormone receptor TR alpha 1. The mice have an average heart rate 20% lower than that of control animals, both under normal conditions and after thyroid hormone stimulation. Electrocardiograms show that the mice also have prolonged QRS- and QTend-durations. The mice have a body temperature 0.5 degrees C lower than normal and exhibit a mild hypothyroidism, whereas their overall behavior and reproduction are normal. The results identify specific and important roles for TR alpha 1 in regulation of tightly controlled physiological functions, such as cardiac pacemaking, ventricular repolarisation and control of body temperature.

Animals↗
PubMed1998

Identification of DNA binding sites for the V-erbA oncoprotein, the viral homolog to thyroid hormone receptor alpha.

The v-erbA oncogene protein, p75(gag-v-erbA), is a mutant form of the thyroid hormone receptor alpha (TR alpha) which has sustained mutations both in the ligand binding and DNA binding domains. The oncoprotein has therefore lost its ability to bind ligand, and its heterodimerization with the retinoid-X receptor (RXR) is impaired. Here, we have investigated the effects of the mutations in the DNA binding domain. By applying a PCR-based screening assay we isolated DNA sequences to which p75(gag-v-erbA) binds as a heterodimer with RXR, and characterized these with regard to their nucleotide sequence and ability to associate with RXR/P75(gag-v-erbA) heterodimers in vitro and in vivo. In the PCR selection assay the heterodimer exhibited a preference for direct repeats with a 3' half-site sequence AGGTCG and spacers of four or five nucleotides separating the two half-sites. These DNA binding data were confirmed by gel retardation assays with synthetic oligonucleotides as well as by transfection experiments using dominantly active VP16 fusion proteins with P75(gag-v-erbA) and TR alpha. The comparison between RXR/P75(gag-v-erbA) and RXR/TR alpha heterodimers demonstrated that although their DNA binding properties are very similar, however, a relaxed specificity of P75(gag-v-erbA) for the spacer length may allow it to interfere with more hormone signalling pathways than only that of thyroid hormone.

Base Sequence↗
PubMed1998

Evidence that decreased heart rate in thyroid hormone receptor-alpha1-deficient mice is an intrinsic defect.

Using a telemetry system with implantable transmitters, we recorded heart rate, electrocardiogram (ECG), body temperature, and locomotor activity continuously in awake, freely moving mice deficient in the thyroid hormone receptor-alpha1 (TRalpha1). We have previously reported that the TRalpha1-deficient mice have a 20% lower mean heart rate and a 0.5 degrees C lower body temperature compared with wild-type control animals. In this study we found that when 3,5, 3'-triiodothyronine (T3) was given once a day, there was a parallel increase in heart rate (occurring 1 day later in the TRalpha1-deficient mice than in controls) and body temperature. Analysis of single-lead ECG revealed a prolonged QRS and Q-Tend time in the TRalpha1-deficient mice, which was shortened after T3 treatment. Monophasic action potential durations, measured in hearts from anesthetized mice at 90% of repolarization, were significantly prolonged in TRalpha1-deficient mice. Air-jet stress and a single injection of an anticholinergic agent induced a parallel increase, and a beta-adrenergic receptor blocker induced a decrease in heart rate in both groups. There was no difference in beta-adrenergic receptor density. The results indicate that the TRalpha1-deficient mice have a specific defect in intrinsic heart rate regulation.

Action Potentials↗
PubMed1998

Requirements for repression of retinoid X receptor by the oncoprotein P75gag-v-erbA and the thyroid hormone receptors.

The oncogenic counterpart of thyroid hormone receptor-alpha (TRRalpha), denoted P75gag-v-erbA, has served as a paradigm for the ability of TRs to repress basal levels of transcription. We show here that the retinoid X receptor (RXR), when activated by its specific ligand SR11237, is repressed by both the normal TRalpha and the P75gag-v-erbA. The repression caused by the two proteins is distinct and dependent on both the cell type and the hormone-response element through which RXR acts. In HeLa cells only TR repressed efficiently through the palindromic 2xIR0 element, whereas the proteins were equally efficient in JEG cells. This demonstrates that proteins distinct in the two cell types mediate the repression. RXR-dependent induction via the natural response element of the cellular retinol-binding protein (CRBPII) gene was likewise (> or = 50%) repressed by TR, whereas P75gag-v-erbA did not repress during the same conditions. Furthermore, P75gag-v-erbA and its variants v-erbAtd359 (lacking repressing activity on TR) and v-erbAr12 (a highly active repressor of TR) efficiently repressed induction by a hybrid protein consisting of the DNA- binding domain of Gal4 and the ligand-binding region of RXR. The viral proteins did not, however, associate with RXR unless the two partners were allowed to heterodimerize upon binding to a specific response element, such as the 2xIR0 element or that of the CRBPII gene. In conclusion, we suggest that the efficient repression seen with the the 2xIR0 element is due to heterodimerization of TR or the viral oncoproteins with RXR and a concomitant inhibition of binding of the RXR-specific ligand that results in an inability of RXR to attract a cell type-specific cofactor. In addition, the data suggest that the interaction between RXR and P75gag-v-erbA on the CRBPII element is too weak to inhibit RXR from binding a ligand and therefore also to repress.

Animals↗
PubMed1997

Chicken thyroid hormone receptor alpha requires the N-terminal amino acids for exclusive nuclear localization.

The subcellular localization of natural and engineered forms of the chicken thyroid hormone receptor (cTR alpha) is dependent on amino acids encoded in the N-terminal region. The full length receptor protein, cTR alpha-p46, was found to localize exclusively to the nucleus, whereas the N-terminally shorter variant, cTR alpha-p40, localizes to both the nucleus and the cytoplasm. The exclusive nuclear localization of cTR alpha-p46 is dependent on the presence of the first 11 N-terminal amino acids, but independent of the phosphorylation of the serine at position 12. Our data identify a novel role for an N-terminal domain of the full length thyroid hormone receptor.

Amino Acid Sequence↗
PubMed1996

The oncoprotein P75gag-v-erbA represses thyroid hormone induced transcription only via response elements containing palindromic half-sites.

The v-erbA oncoprotein P75gag-v-erbA, derived from the thyroid hormone receptor alpha (TR alpha), functions as a transdominant transcriptional repressor. The mechanism by which P75gag-v-erbA acts is however poorly characterized. Here, we show that repression of TR alpha mediated transcription by P75gag-v-erbA in transformed erythroblasts is dependent on the structure of the thyroid hormone response element to which it binds. A very efficient repression was seen with hormone response elements having half-sites organized as everted repeats (ER), whereas repression was inefficient with directly repeated half-sites (DR). Promoters containing half-sites organized as an inverted palindrome (IR) gave an intermediate repression. Although P75gag-v-erbA failed to associate with the ligand binding domain of retinoid X (RXR) receptor in a two-hybrid test, the oncoprotein in nuclear extracts from transformed cells heterodimerised quantitatively with RXR upon binding to response elements of the DR type. On the other hand, both RXR/P75gag-v-erb heterodimers and other types of dimers formed on ER elements. P75gag-v-erbA also failed to bind to elements that contained only one half-site in vivo and in vitro. The data demonstrate that P75gag-v-erbA represses gene expression efficiently as a dimer, and suggest that thyroid hormone responsive genes that may be targets for the action of the oncoprotein are repressed most efficiently if they contain elements of the ER type.

Base Sequence↗
PubMed1996

Transactivation by the thyroid hormone receptor is dependent on the spacer sequence in hormone response elements containing directly repeated half-sites.

The thyroid hormone receptor (TR) regulates the transcription of its target genes by interacting with specific hormone response elements consisting usually of directly repeated half-sites with the consensus sequence AGGTCA. To investigate the role of the spacer sequences separating the half-sites, heterodimers formed by TRalpha and the retinoid-X receptor (RXR) were used in a PCR based selection and amplification assay. The TRalpha/RXR heterodimer selected for elements with directly repeated half-sites having a spacer of 4 nucleotides (DR4). Preferences for nucleotides in the TR binding half-site motif as well as for the 4 nucleotides separating the two half-sites were found. DNA binding and transfection studies using DR4 elements with different spacer sequences showed the importance of these nucleotides for the activity of the response element: some spacer sequences allowed little or no transactivation from the element, whereas other sequences supported strong transactivation. A pyrimidine nucleotide in position three of the spacer enhanced TRalpha binding and transactivation. Additional experiments showed that heterodimers between RXR and other putative receptors exhibited a similar but distinct specificity for the spacer sequence. Our results thus suggest that the four nucleotides separating the two half-sites in hormone response elements have a major role in determining induction of hormone responsive genes.

Base Sequence↗
PubMed1995

Altered expression after expansion of a v-erbA transgene in transgenic mice.

Repetitive DNA is known to undergo size variations based on an increase or decrease in the number of monomer units. We describe here the spontaneous expansion of an experimentally introduced tandem array of repeats in a transgenic mouse consisting of the human beta-actin promoter fused to the viral oncogene v-erbA and an SV40 polyadenylation signal (hAP/v-erbA). The expansion of the transgene was identified during routine screening of transgenic offspring for heterozygosity or homozygosity in one founder line. The control heterozygote genome consisted of the hAP/v-erbA transgene organized as a tandem array approximately five monomer units at a single chromosomal locus. The number of units increased to 20-21 copies, and germline transmission of the expanded units was stable for at least two generations. The majority of animals carrying the expanded monomer units retained their RNA expression patterns; however, some of these animals had drastically reduced expression levels. We discuss the possibility that expansion of repeated units may provide a mechanism by which the expression of a deleterious transgene is reduced.

Actins↗
PubMed1995

Ligand-dependent and -independent transactivation by thyroid hormone receptor beta 2 is determined by the structure of the hormone response element.

Chicken thyroid hormone receptor beta 2 (cTR beta 2) is likely to serve specific functions in gene regulation since it possesses a unique N-terminal domain and is expressed in very few tissues. We demonstrate here that TR beta 2 exhibits distinct transactivation properties which are dependent on the availability of ligand and on the structure of the hormone response element. First, a strong ligand-independent transactivation was observed with hormone response elements composed of direct repeats and everted repeats. Second, TR beta 2 was induced by triiodothyronine to transactivate more efficiently than TR beta 0 on palindromic and everted-repeat types of hormone response elements. However, coexpression of the retinoid X receptor reduced the strong transactivation by TR beta 2 but not by TR beta 0 via palindromic response elements, suggesting that TR beta 2 can transactivate as a homodimer. Finally, the N terminus of TR beta 2 contains two distinct transactivation regions rich in tyrosines, which are essential for transactivation. Our results thus show that the activity of the novel transactivating region of TR beta 2 is dependent on the organization of the half-sites in the response element.

Amino Acid Sequence↗
PubMed1994

Thyroid abnormalities and hepatocellular carcinoma in mice transgenic for v-erbA.

The v-erbA oncogene consists of an avian retroviral gag gene fused to a mutated thyroid hormone receptor. To define better its role as an oncogene in mammals and its ability to function as a dominant negative transcription factor, transgenic mice expressing v-erbA ubiquitously were generated. The effects of v-erbA are pleiotropic, tissue-specific and dose dependent. Mice have breeding disorders, abnormal behavior, reduced adipose tissue, hypothyroidism with inappropriate TSH response, and enlarged seminal vesicles. This provides an animal model consistent with the proposal that v-ErbA functions as a dominant negative receptor by transcriptional interference or squelching of normal receptors or associated proteins. Finally, male animals develop hepatocellular carcinoma, demonstrating that v-erbA can promote neoplasia in mammals.

Adipose Tissue↗