DNA-dependent cofactor selectivity of the glucocorticoid receptor.
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Amino Acid Sequence↗
Biomedical subjects
T Heinzel
Publications and source records attributed to T Heinzel.
Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells.
Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the well-tolerated antiepileptic drug valproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC-dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Valproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients. More over, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy.
Animals↗
Energy spectra of quantum rings.
Quantum mechanical experiments in ring geometries have long fascinated physicists. Open rings connected to leads, for example, allow the observation of the Aharonov-Bohm effect, one of the best examples of quantum mechanical phase coherence. The phase coherence of electrons travelling through a quantum dot embedded in one arm of an open ring has also been demonstrated. The energy spectra of closed rings have only recently been studied by optical spectroscopy. The prediction that they allow persistent current has been explored in various experiments. Here we report magnetotransport experiments on closed rings in the Coulomb blockade regime. Our experiments show that a microscopic understanding of energy levels, so far limited to few-electron quantum dots, can be extended to a many-electron system. A semiclassical interpretation of our results indicates that electron motion in the rings is governed by regular rather than chaotic motion, an unexplored regime in many-electron quantum dots. This opens a way to experiments where even more complex structures can be investigated at a quantum mechanical level.
Journal Article↗
Shot noise by quantum scattering in chaotic cavities.
We have experimentally studied shot noise of chaotic cavities defined by two quantum point contacts in series. The cavity noise is determined as (1/4)2e/I/ in agreement with theory and can be well distinguished from other contributions to noise generated at the contacts. Subsequently, we have found that cavity noise decreases if one of the contacts is further opened and reaches nearly zero for a highly asymmetric cavity. Heating inside the cavity due to electron-electron interaction can slightly enhance the noise of large cavities and is also discussed quantitatively.
Journal Article↗
Signatures of spin pairing in chaotic quantum dots.
Coulomb blockade resonances are measured in a GaAs quantum dot in which both shape deformations and interactions are small. The parametric evolution of the Coulomb blockade peaks shows a pronounced pair correlation in both position and amplitude, which is interpreted as spin pairing. As a consequence, the nearest-neighbor distribution of peak spacings can be well approximated by a modified bimodal Wigner surmise, in which interactions are taken into account beyond the constant interaction model.
Journal Article↗
Multiple regions of ETO cooperate in transcriptional repression.
In acute myeloid leukemias (AMLs) with t(8;21), the transcription factor AML1 is juxtaposed to the zinc finger nuclear protein ETO (Eight-Twenty-One), resulting in transcriptional repression of AML1 target genes. ETO has been shown to interact with corepressors, such as N-CoR and mSin3A to form complexes containing histone deacetylases. To define regions of ETO required for maximal repressor activity, we analyzed amino-terminal deletions in a transcriptional repression assay. We found that ETO mutants lacking the first 236 amino acids were not affected in their repressor activity, whereas a further deletion of 85 amino acids drastically reduced repressor function and high molecular weight complex formation. This latter mutant can still homodimerize and bind to N-CoR but shows only weak binding to mSin3A. Furthermore, we could show that a "core repressor domain" comprising nervy homology region 2 and its amino- and carboxyl-terminal flanking sequences recruits mSin3A and induces transcriptional repression. These results suggest that mSin3A and N-CoR bind to ETO independently and that both binding sites cooperate to maximize ETO-mediated transcriptional repression. Thus, ETO has a modular structure, and the interaction between the individual elements is essential for the formation of a stable repressor complex and efficient transcriptional repression.
Amino Acids↗
Histone deacetylase as a therapeutic target.
The maintenance of health depends on the coordinated and tightly regulated expression of genetic information. Certain forms of leukemia have become paradigms for the pathogenic role of aberrant repression of differentiation genes. In these acute leukemias, fusion proteins generated by chromosomal translocations no longer function as transcriptional activators, but instead repress target genes by recruiting histone deacetylases (HDACs). The potential benefit of HDAC inhibition has been established by the use of enzyme inhibitors in vitro and in a single reported case of experimental therapy. Because recently identified HDAC inhibitors appear to overcome many drawbacks of early inhibitory compounds in clinical use, the stage is set to test the therapeutic value of HDAC inhibition in leukemias and in other diseases, including solid tumors and aberrant hormonal signaling. This review summarizes the range of diseases expected to respond to HDAC inhibition.
Acute Disease↗
Analysis of the metallic phase of two-dimensional holes in SiGe in terms of temperature dependent screening
We find that temperature dependent screening can quantitatively explain the metallic behavior of the resistivity on the metallic side of the so-called metal-insulator transition in p-SiGe. Interference and interaction effects exhibit the usual insulating behavior which is expected to overpower the metallic background at sufficiently low temperatures. We find empirically that the concept of a Fermi liquid describes our system with its large interaction parameter r(s) approximately 8.
Journal Article↗
VDR-Alien: a novel, DNA-selective vitamin D(3) receptor-corepressor partnership.
The vitamin D receptor (VDR) is a transcription factor that transmits incoming 1,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) signaling via combined contact with coactivator proteins and specific DNA binding sites (VDREs), which ultimately results in activation of transcription. In contrast, the mechanisms of transcriptional repression via the VDR are less well understood. This study documents VDR-dependent transcriptional repression largely via histone deacetylase (HDAC) activity. Direct, ligand-sensitive protein-protein interaction of the VDR with the nuclear receptor corepressor (NCoR) and a novel corepressor, called Alien, was demonstrated to be comparable but independent of the VDR AF-2 trans-activation domain. Functional assays indicated that Alien, but not NCoR, displays selectivity for different VDRE structures for transferring these repressive effects into gene regulatory activities. Moreover, superrepression via Alien was found to be affected only in part by HDAC inhibitors such as trichostatin A. Finally, for a dissociation of VDR-Alien complexes in vitro and in vivo, higher ligand concentrations were needed than for a dissociation of VDR-NCoR complexes. This suggests that Alien and NCoR are using different interfaces for interaction with the VDR and different pathways for mediating superrepression, which in turn characterizes Alien as a representative of a new class of corepressors. Taken together, association of the VDR with corepressor proteins provides a further level of transcriptional regulation, which is emerging as a complex network of protein-protein interaction-mediated control.
Animals↗
The fermionic hanbury brown and twiss experiment
A Hanbury Brown and Twiss experiment for a beam of electrons has been realized in a two-dimensional electron gas in the quantum Hall regime. A metallic split gate serves as a tunable beam splitter to partition the incident beam into transmitted and reflected partial beams. In the nonequilibrium case the fluctuations in the partial beams are shown to be fully anticorrelated, demonstrating that fermions exclude each other. In equilibrium, the cross-correlation of current fluctuations at two different contacts is also found to be negative and nonzero, provided that a direct transmission exists between the contacts.
Journal Article↗
Signal-specific co-activator domain requirements for Pit-1 activation.
POU-domain proteins, such as the pituitary-specific factor Pit-1, are members of the homeodomain family of proteins which are important in development and homeostasis, acting constitutively or in response to signal-transduction pathways to either repress or activate the expression of specific genes. Here we show that whereas homeodomain-containing repressors such as Rpx2 seem to recruit only a co-repressor complex, the activity of Pit-1 is determined by a regulated balance between a co-repressor complex that contains N-CoR/SMRT, mSin3A/B and histone deacetylases, and a co-activator complex that includes the CREB-binding protein (CBP) and p/CAF. Activation of Pit-1 by cyclic AMP or growth factors depends on distinct amino- and carboxy-terminal domains of CBP, respectively. Furthermore, the histone acetyltransferase functions of CBP or p/CAF are required for Pit-1 function that is stimulated by cyclic AMP or growth factors, respectively. These data show that there is a switch in specific requirements for histone acetyltransferases and CBP domains in mediating the effects of different signal-transduction pathways on specific DNA-bound transcription factors.
Acetyltransferases↗
Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes.
Several lines of evidence indicate that the nuclear receptor corepressor (N-CoR) complex imposes ligand dependence on transcriptional activation by the retinoic acid receptor and mediates the inhibitory effects of estrogen receptor antagonists, such as tamoxifen, suppressing a constitutive N-terminal, Creb-binding protein/coactivator complex-dependent activation domain. Functional interactions between specific receptors and N-CoR or SMRT corepressor complexes are regulated, positively or negatively, by diverse signal transduction pathways. Decreased levels of N-CoR correlate with the acquisition of tamoxifen resistance in a mouse model system for human breast cancer. Our data suggest that N-CoR- and SMRT-containing complexes act as rate-limiting components in the actions of specific nuclear receptors, and that their actions are regulated by multiple signal transduction pathways.
Animals↗
A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression.
Transcriptional repression by nuclear receptors has been correlated to binding of the putative co-repressor, N-CoR. A complex has been identified that contains N-CoR, the Mad presumptive co-repressor mSin3, and the histone deacetylase mRPD3, and which is required for both nuclear receptor- and Mad-dependent repression, but not for repression by transcription factors of the ets-domain family. These data predict that the ligand-induced switch of heterodimeric nuclear receptors from repressor to activator functions involves the exchange of complexes containing histone deacetylases with those that have histone acetylase activity.
Animals↗
Differential effects of nuclear receptor corepressor (N-CoR) expression levels on retinoic acid receptor-mediated repression support the existence of dynamically regulated corepressor complexes.
Thyroid hormone and retinoic acid receptors are members of the nuclear receptor superfamily of ligand-dependent transcription factors that stimulate the transcription of target genes in the presence of activating ligands and repress transcription in their absence. Transcriptional repression by the thyroid hormone and retinoic acid receptors has been proposed to be mediated by the nuclear receptor corepressor, N-CoR, or the related factor, SMRT (silencing mediator of retinoic acid and thyroid hormone receptors). Recent studies have suggested that transcriptional repression by N-CoR involves a corepressor complex that also contains mSin3A/B and the histone deacetylase, RPD3. In this manuscript, we demonstrate that transcriptional repression by the retinoic acid receptor can be either positively or negatively regulated by changes in the levels of N-CoR expression, suggesting a relatively strict stoichiometric relationship between N-CoR and other components of the corepressor complex. Consistent with this interpretation, overexpression of several functionally defined domains of N-CoR also relieve repression by nuclear receptors. N-CoR is distributed throughout the nucleus in a nonuniform pattern, and a subpopulation becomes concentrated into several discrete dot structures when highly expressed. RPD3 is also widely distributed throughout the nucleus in a nonuniform pattern. Simultaneous imaging of RPD3 and N-CoR suggest that a subset of each of these proteins colocalize, consistent with the existence of coactivator complexes containing both proteins. In addition, a substantial fraction of both N-CoR and mSin3 A/B appear to be independently distributed. These observations suggest that interactions between RPD3 and Sin3/N-CoR complexes may be dynamically regulated.
Animals↗
A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors.
Nuclear receptors regulate gene expression by direct activation of target genes and inhibition of AP-1. Here we report that, unexpectedly, activation by nuclear receptors requires the actions of CREB-binding protein (CBP) and that inhibition of AP-1 activity is the apparent result of competition for limiting amounts of CBP/p300 in cells. Utilizing distinct domains, CBP directly interacts with the ligand-binding domain of multiple nuclear receptors and with the p160 nuclear receptor coactivators, which upon cloning have proven to be variants of the SRC-1 protein. Because CBP represents a common factor, required in addition to distinct coactivators for function of nuclear receptors, CREB, and AP-1, we suggest that CBP/p300 serves as an integrator of multiple signal transduction pathways within the nucleus.
Animals↗
Coulomb-blockade oscillations in a quantum dot strongly coupled to leads.
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Journal Article↗
Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor.
Thyroid-hormone and retinoic-acid receptors exert their regulatory functions by acting as both activators and repressors of gene expression. A nuclear receptor co-repressor (N-CoR) of relative molecular mass 270K has been identified which mediates ligand-independent inhibition of gene transcription by these receptors, suggesting that the molecular mechanisms of repression by thyroid-hormone and retinoic-acid receptors are analogous to the co-repressor-dependent transcriptional inhibitory mechanisms of yeast and Drosophila.
Amino Acid Sequence↗
Single electron switching in a parallel quantum dot.
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Journal Article↗