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Biomedical subjects

F Horn

Publications and source records attributed to F Horn.

At least 55 records · Page 3Linked to original sources
PubMed1996

Differential activation of acute phase response factor/STAT3 and STAT1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130. I. Definition of a novel phosphotyrosine motif mediating STAT1 activation.

Interleukin-6 (IL-6) and gamma-interferon (IFNgamma) activate an overlapping set of genes via the Jak/STAT pathway. However, at least in human cells, a differential activation of STAT transcription factors was observed: IL-6 activates both acute phase response factor (APRF)/STAT3 and STAT1, whereas IFNgamma leads only to STAT1 activation. All STATs cloned so far contain SH2 domains. Since all cytokine receptors using the Jak/STAT pathway were found to be tyrosine-phosphorylated after ligand binding, it has been proposed that specific phosphotyrosine modules within the cytoplasmic domain of the receptor chains recruit different STAT factors. We have analyzed by mutational studies and by phosphopeptide competition assays which of the tyrosine modules of the IL-6 signal transducer gp130 are capable of recruiting either APRF or STAT1. We found that two of the four tyrosine modules that are important for APRF activation also activate STAT1. For these modules, we propose the new consensus sequence YXPQ. We further present evidence that STAT1 is activated independently from APRF suggesting that gp130 contains multiple independent STAT binding sites. We compare the APRF and STAT1 activation motifs of gp130 with the STAT1 activation motif of the IFNgamma receptor and demonstrate that the specificity of activation can be changed from APRF to STAT1 and vice versa by only two point mutations within a tyrosine module. These data strongly support the concept that the activation of a specific STAT is determined mainly by the phosphotyrosine module. The significance of these findings for other receptor systems is discussed.

Acute-Phase Proteins↗
PubMed1996

Differential activation of acute phase response factor/Stat3 and Stat1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130. II. Src homology SH2 domains define the specificity of stat factor activation.

Distinct yet overlapping sets of STAT transcription factors are activated by different cytokines. One example is the differential activation of acute phase response factor (APRF, also called Stat3) and Stat1 by interleukin 6 and interferon-gamma. Interleukin 6 activates both factors while, at least in human cells, interferon-gamma recruits only Stat1. Stat1 activation by interferon-gamma is mediated through a cytosolic tyrosine motif, Y440, of the interferon-gamma receptor. In an accompanying paper (Gerhartz, C., Heesel, B., Sasse, J., Hemmann, U., Landgraf, C., Schneider-Mergener, J., Horn, F., Heinrich, P. C., and Graeve, L. (1996) J. Biol. Chem. 271, 12991-12998), we demonstrated that two tyrosine motifs within the cytoplasmic part of the interleukin 6 signal transducer gp130 specifically mediate APRF activation while two others can recruit both APRF and Stat1. By expressing a series of Stat1/APRF domain swap mutants in COS-7 cells, we now determined which domains of Stat1 and APRF are involved in the specific recognition of phosphotyrosine motifs. Our data demonstrate that the SH2 domain is the sole determinant of specific STAT factor recruitment. Furthermore, the SH2 domain of Stat1 is able to recognize two unrelated types of phosphotyrosine motifs, one represented by the interferon-gamma receptor Y440DKPH peptide, and the other by two gp130 YXPQ motifs. By molecular modeling, we propose three-dimensional model structures of the Stat1 and APRF SH2 domains which allow us to explain the different binding preferences of these factors and to predict amino acids crucial for specific peptide recognition.

Acute-Phase Proteins↗
PubMed1996

JAKs, STATs and signal transduction in response to the interferons and other cytokines.

The isolation and complementation of mutant human cell lines has established an essential role for the JAK (Janus kinase) family of protein tyrosine kinases and STAT (signal transduction and transcription) factors in the Interferon response pathways. Activation of STATs by JAKs occurs in receptor complexes at the cell membrane. Activated STATs form homo- or heterodimers and, with or without additional factors, migrate to the nucleus to initiate transcription. Different STAT combinations interact differentially with related DNA response elements. Signalling pathways of this novel type are likely utilized by a wide variety of polypeptide ligands. Data from the IL2, IL6 and IFN systems indicate a major role for the tyrosine phosphorylated receptor/JAK complexes (rather than substrate specificity of the JAKs per se) in STAT selection. The mutant cell lines lacking individual JAKs and STATs are being used together with kinase-negative JAK mutants which differentially affect the IFN-gamma, and IFN-alpha beta and IL-6 pathways in the further analysis of these and additional systems.

Cytokines↗
PubMed1996

Quadrant pattern ERG with SLO stimulation in normals and glaucoma patients.

BACKGROUND: The pattern ERG (PERG) is one of the promising methods for investigation of glaucoma and may detect it at an early stage. The purpose of this study was to test the usefulness of the scanning laser ophthalmoscope (SLO) as a stimulator for evoking quadrant PERGs under visual control in normal and glaucoma eyes. METHODS: The helium-neon laser of a Rodenstock SLO was used for quadrant stimulation (18 degrees x 29 degrees pattern size), while an infrared laser visualized the eye's fundus. Steady-state pattern-reversal ERGs were recorded in response to stripe patterns (8.33 Hz, 0.5 cycles/deg) in four retinal quadrants. Corresponding visual field defects were determined with the Octopus perimeter (G1, peridata). The subjects were 28 controls and 34 glaucoma patients with visual field losses and papillometric defects. RESULTS: Amplitudes of nasal retinal areas (which include the blind spot) are smaller than those of temporal ones, and temporal lower responses are the largest. PERG amplitudes of all quadrants are significantly reduced in glaucoma (sensitivity 82%, specificity 80%). The differences between upper and lower quadrant PERGs are correlated with the differences between localized visual field defects of the same areas, (r = 0.46, P = 0.02). CONCLUSIONS: The study demonstrates the feasibility of the SLO system for evoking localized PERG in normals and patients and shows the reduction of quadrant ERG amplitudes in glaucoma using the laser system.

Adult↗
PubMed1996

Comparison of the effects of insulin, PDGF, interleukin-6, and interferon-gamma on glucose transport in 3T3-L1 cells: lack of cross-talk between tyrosine kinase receptors and JAK/STAT pathways.

The effects of insulin, insulin-like growth factor (IGF)-I, platelet-derived growth factor (PDGF), interleukin (IL)-6 and interferon-gamma on 2-deoxyglucose uptake and insulin receptor substrate (IRS)-1 phosphorylation were compared in 3T3-L1 cells at confluence and after differentiation to the adipocyte-like phenotype. Insulin and IGF-I produced the expected stimulation of glucose transport and tyrosine phosphorylation of IRS-1 in both confluent and differentiated cells. In contrast, IL-6 and interferon-gamma failed to stimulate glucose transport or IRS-1 phosphorylation, although a marked stimulation of the JAK/STAT pathways as shown by acute-phase response factor (APRF)/Stat3 or Stat1 activation was observed in fibroblasts (IL-6, interferon-gamma) and adipocytes (IL-6). PDGF-AA and PDGF-BB stimulated glucose transport in confluent, undifferentiated cells to the same extent as insulin (approximately six-fold stimulation), but produced only a small portion of the effect of insulin in differentiated cells. Similarly, mRNA levels and autophosphorylation of PDGF receptors were much lower in differentiated cells than in confluent fibroblasts. In contrast to insulin and IGF-I, PDGF failed to stimulate tyrosine phosphorylation of IRS-1. All effects of insulin, IGF-I, and PDGF on glucose transport were inhibited by Wortmannin; the half-maximally inhibiting concentration (IC50) of Wortmannin was increased by insulin. These data demonstrate distinct signalling potentials of the investigated receptors, and indicate that the IL-6 and interferon-gamma controlled JAK/STAT pathways lack the potential to stimulate glucose transport. IRS-1 does not appear to be involved in the PDGF receptor-mediated effects, whereas activation of phosphatidylinositol (PI) 3-kinase is a crucial event in all pathways leading to stimulation of glucose transport.

3T3 Cells↗
PubMed1996

A role for calcineurin in Dictyostelium discoideum development.

We have used the immunosuppressants cyclosporin A and FK506 to investigate the involvement of the Ca2+/CaM-dependent protein phosphatase calcineurin in Dictyostelium discoideum development. We found that CsA had little effect on cell growth, or on the aggregation of developing amoebae, suggesting that calcineurin does not play a significant role at these stages of the D. discoideum life cycle. In contrast, when cells were allowed to differentiate under buffer in the presence of cAMP, addition of CsA and FK506 strongly inhibited stalk cell formation in the wild-type and spore formation in a sporogenous derivative of D. discoideum strain V12. These agents also reduced the expression of prestalk-and prespore-specific transcripts in both strains. These results indicate a requirement for calcineurin activity in both pathways of cell differentiation. In addition, time-course experiments suggest that calcineurin is required early in the differentiation processes, but that the maturation of the two cell types is resistant to calcineurin inhibition. We also found that CsA and FK506 were unable to affect spore formation in rapidly developing/sporogenous rdeC mutants of strain NC4, showing that constitutive cAMP-dependent protein kinase activity renders the spore pathway resistant to calcineurin inhibition.

Animals↗
PubMed1996

[Sensory physiology and biomorphology of the optic papilla: analysis of correlation in normal persons].

BACKGROUND: The aim of the present study was to investigate whether the morphological variability of the optic disc has an influence on sensory test procedures. PATIENTS AND METHODS: In 52 eyes of 52 normal persons psychophysical (perimetry, color vision, contrast sensitivity) and electrophysiological (pattern-ERG and pattern-VEP) tests and planimetric papillometry were performed. A correlation analysis was made between sensory tests and area of optic disc (1.79 to 5.2 mm2) and neuroretinal rim. RESULTS: There was no significant correlation between perimetry, color vision, pattern-ERG, pattern-VEP, spatio-temporal and temporal contrast sensitivity on the one hand and optic disc area or neuroretinal rim area on the other. CONCLUSION: Results of psychophysical and electrophysiological tests do not have to be corrected with respect to the neuroretinal rim area.

Adult↗
PubMed1996

Contrast-sensitivity testing with scanning-laser ophthalmoscope stimulation in normal, ocular hypertensive, and glaucomatous patients.

The purpose of this study was to test the usefulness of the scanning laser ophthalmoscope (SLO) as a stimulator for localized contrast-sensitivity (CS) measurements under visual control in normals and glaucomatous patients. The helium-neon laser (630 nm) of a Rodenstock SLO was used to generate a localized square-wave stripe pattern and a fixation mark while an infrared laser (780 nm) visualized the eye's fundus. Thus, measurements with unstable fixation could be discarded. The spatio-temporal CS was determined with a localized alternating pattern as follows: 5 Hz, 2.88 cycles/degree; stimulus diameter 2 degrees; test location central, temporal upper, and temporal lower retinal area. The subjects included 47 controls, 23 ocular hypertensive patients (intraocular pressure > 21 mmHg, normal optic disc, no visual field defect), 27 "preperimetric" glaucoma patients (intraocular pressure > 21 mmHg, early glaucomatous optic disc damage, no visual field defect), and 41 "perimetric" glaucoma patients with glaucomatous defects of the optic disc and perimetric losses. Nonparametric tests (Wilcoxon, Spearman) were used for statistical analyses. Among the three locations tested, CS values recorded for the temporal lower retinal areas showed the strongest reduction in glaucomas ("preperimetric" P = 0.002, "perimetric" P < 0.0001) and a significant correlation with the perimetric mean defect of the stimulated area (r = 0.65, P < 0.001). In all, 95% of glaucomatous eyes with extensive visual field losses were recognized as pathologic at a specificity of 80%. Spatiotemporal CS of temporal retinal areas is sensitive to glaucoma. The present study confirms the feasibility of using the SLO system for localized CS measurements, in normals and patients.

Adult↗
PubMed1995

A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6.

The protein tyrosine kinases JAK1, JAK2 and Tyk2 and STATs (signal transducers and activators of transcription) 1 and 3 are activated in response to interleukin-6 (IL-6) in human fibrosarcoma cells. In mutant cells lacking JAK1, JAK2 or Tyk2, the absence of one kinase does not prevent activation of the others; activation does not, therefore, involve a sequential three-kinase cascade. In the absence of JAK1, the phosphorylation of the gp130 subunit of the IL-6 receptor and the activation of STATs 1 and 3 are greatly reduced. JAK1 is also necessary for the induction of IRF1 mRNA, thus establishing a requirement for the JAK/STAT pathway in the IL-6 response. JAK2 and Tyk2 although activated cannot, in the absence of JAK1, efficiently mediate activation of STATs 1 and 3. A kinase-negative mutant of JAK2 can, however, inhibit such activation, and ancillary roles for JAK2 and Tyk2 are not excluded. A major role for JAK1 and the nonequivalence of JAK1 and JAK2 in the IL-6 response pathway are, nevertheless, clearly established for these cells.

Adolescent↗
PubMed1995

Transcriptional regulation of the junB promoter: analysis of STAT-mediated signal transduction.

The product of the junB gene is a member of the AP-1 family of transcription factors that activate transcription by binding to TPA-responsive elements (TREs) within the promoters of target genes. Components of AP-1 are immediate-early genes whose expression is upregulated by a plethora of extracellular stimuli and are important in mediating cellular proliferation and differentiation. Such stimuli include the pleiotropic cytokine interleukin-6 (IL-6) which plays a role in immune and inflammatory responses and ciliary neurotrophic factor (CNTF) which enhances survival and differentiation of neurons and glia. We have analysed expression from junB promoter-CAT reporter constructs in HepG2 cells and found that a region between -196 and -91 can mediate response to IL-6 and CNTF and was able to confer responsiveness to a heterologous promoter. We further show by gel retardation analysis that distinct nuclear factors induced by IL-6 specifically bind to this interleukin-6 response element (IRE). This region contains both a putative ETS- and a STAT-transcription factor binding site. We show by mutational analysis and supershift data that the IL-6 induced complex indeed contains the transcription factor APRF/Stat3 that is both necessary and sufficient for activation. Interestingly this site does not appear to bind Stat1 itself, as shown by supershift analysis and a lack of response to IFN-gamma both at the DNA-binding and transcriptional level. Furthermore, we demonstrate that the junB IRE-binding activity induced by IL-6 requires tyrosine kinase activity, whereas induced transactivation of IRE-constructs additionally occurs through an H7-sensitive pathway that is p21ras-independent, implicating serine/threonine kinases in the transactivation of IRE-binding factors.

Animals↗
PubMed1995

Interleukin-6-induced serine phosphorylation of transcription factor APRF: evidence for a role in interleukin-6 target gene induction.

The cytokine interleukin-6 (IL-6) rapidly activates a latent cytoplasmic transcription factor, acute-phase response factor (APRF), by tyrosine phosphorylation. Activation and DNA binding of APRF are inhibited by inhibitors of protein tyrosine kinases but not serine/threonine kinases. However, immediate-early gene induction by IL-6 and, as we show here, stimulation of the promoters of the genes for alpha 2-macroglobulin, Jun-B, and intercellular adhesion molecule-1 (ICAM-1) are blocked by the serine/threonine kinase inhibitor H7. We now show that IL-6 triggers a delayed phosphorylation of APRF at serine resudues which can be reversed in vitro by protein phosphatase 2A and is also inhibited by H7. Therefore, APRF serine phosphorylation is likely to represent a crucial event in IL-6 signal transduction leading to target gene induction.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1995

Comparison of temporal and spatiotemporal contrast-sensitivity tests in normal subjects and glaucoma patients.

Contrast sensitivity (CS) is reduced in glaucoma diseases. This study compares the value of different CS measurements in glaucoma diagnosis. The study population consisted of age-matched groups of 31 normal subjects (age, 36-59 years; median, 47 years; mean +/- SD, 47.4 +/- 7 years) and 59 glaucoma patients with optic disk damage and visual field defects (age, 36-63 years; median, 53 years; mean +/- SD, 52.3 +/- 7 years). Three types of CS determination were carried out in all subjects: (1) temporal CS of a sinusoidally flickering light (37 Hz) in a ganzfeld bowl, (2) spatiotemporal CS (alternating pattern: 2.5 Hz, 1 cycle/degree; screen size, 5.3 degrees x 4.3 degrees) in a temporal upper retinal area (13.8 degrees horizontal, 4.2 degrees vertical), and (3) spatial CS of a static pattern (three spatial frequencies: 0.6, 3.0, and 12 cycles/degree; screen size, 5.3 degrees x 4.3 degrees) with central fixation. In glaucoma patients the results of CS tests with flickering stimuli were highly significantly correlated with the perimetric mean sensitivity (MS; Octopus G1 program: temporal CS, r = 0.67, P < 0.001; spatiotemporal CS, r = 0.8, P < 0.001). For spatial CS the frequency of 3.0 cycles/degree showed the strongest correlation with MS (r = 0.64, P < 0.001). Only the peripherally localized, spatiotemporal CS showed a strong correlation with optic disk damage (r = 0.59, P < 0.001). On the other hand, the full-field flicker test achieved the best separation between normal subjects and glaucoma patients (specificity, 90%; sensitivity, 71%). These results indicate that tests for temporal resolution are more sensitive to glaucoma defects than are tests for spatial resolution.

Adult↗
PubMed1994

Stimulation of the human intercellular adhesion molecule-1 promoter by interleukin-6 and interferon-gamma involves binding of distinct factors to a palindromic response element.

Intercellular adhesion molecule-1 (ICAM-1) is a transmembrane glycoprotein that promotes adhesion in immunological and inflammatory reactions. ICAM-1 is expressed on cells of many lineages and is induced by interleukin-6 (IL-6) and interferon-gamma (IFN-gamma). Functional analysis of ICAM-1 promoter-luciferase constructs in HepG2 cells enabled us to identify a region between -110 and -37 mediating IL-6 and IFN-gamma responsiveness and containing a palindromic IL-6/IFN-gamma response element (pIRE). Site-directed mutagenesis of key nucleotides in the ICAM-1 pIRE abolished the effect of both IL-6 and IFN-gamma stimulation, while this pIRE element was sufficient to confer IL-6 and IFN-gamma responsiveness to a heterologous promoter. We further show by gel retardation analysis that distinct nuclear factors induced by both IL-6 or IFN-gamma specifically bind to this pIRE. Furthermore, treatment with IL-6 results in the formation of multiple complexes while IFN-gamma induces a single binding complex, both in HepG2 and monocytic U937 cells. Differentiation of U937 cells by exposure to 12-O-tetradecanoyl phorbol-13-acetate abolishes response to IL-6 but not IFN-gamma. Supershift data utilizing the ICAM-1 pIRE revealed that IFN-gamma and IL-6 both induce a factor antigenically related to IFN-gamma activation factor. We further provide data suggesting that IL-6 additionally activates an ICAM-1 pIRE binding factor related to the previously described acute-phase response factor in disparate cell types. We therefore conclude that the activation of these related nuclear factors by IL-6 and IFN-gamma is important in the regulation of ICAM-1 gene expression.

Base Sequence↗
PubMed1994

Differences between pattern-evoked electroretinograms obtained by a scanning laser ophthalmoscope and by a mechanical mirror system.

Pattern electroretinograms were studied in response to stripe patterns of different spatial frequencies and intensities in the pattern-onset and reversal mode by means of a scanning laser ophthalmoscope and a mechanical mirror system (maxwellian view). The stimulus conditions in both procedures were as close as possible: 31 degrees square field, 633-nm wavelength and the same equipment for recording. The remaining differences between the two methods were the line and pixel structure in the scanning laser ophthalmoscope and the buildup speed (40 ms in the scanning laser ophthalmoscope and less than 1 ms in the mirror system). This difference was reflected in the response peak times of the pattern electroretinogram, which were up to 10 ms in the scanning laser ophthalmoscope measurement. The pattern-related onset response was smaller with the scanning laser ophthalmoscope, indicating a strong sensitivity to the slow build-up speed, while the offset and reversal responses showed no differences in amplitudes. All differences were found only with the use of high luminances. The results suggest that responses evoked with patterns displayed on a television screen could be faster and larger if stimulators faster than the conventional television standard were used. Because of the smallness of onset amplitudes, the pattern-reversal mode might be better for stimulation in a clinical study when the scanning laser ophthalmoscope is used.

Adult↗
PubMed1994

Cytokines and growth factors signal through tyrosine phosphorylation of a family of related transcription factors.

The ability of cytokines to activate distinct but overlapping sets of genes defines their characteristic biological response. We now show that IFN gamma, IL-3, IL-4, IL-6, erythropoietin, EGF, and CSF-1 activate differing members of a family of latent cytoplasmic transcription factors. Although these factors have distinct physical and functional properties and exhibit different patterns of expression, they share many important features, including recognition of a related set of enhancer elements, rapid activation, tyrosine phosphorylation, and cross-reactivity to antibodies against p91, a cytoplasmic signaling protein activated by IFN alpha, IFN gamma, and IL-6. These shared features point to either parallel or common patterns of signal transduction. A general model of cytokine signal transduction is presented, in which receptor-associated tyrosine kinases activate ligand-specific members of a family of signal-transducing factors. Once activated, these factors carry their signals to the nucleus, where they bind a family of related enhancer elements.

Base Sequence↗
PubMed1994

A factor induced by differentiation signals in cells of the macrophage lineage binds to the gamma interferon activation site.

Rapid transcriptional induction of genes in response to gamma interferon (IFN-gamma) is mediated by the IFN-gamma activation site (GAS) and its cognate protein, the IFN-gamma activation factor (GAF). We describe a GAS-associated, differentiation-induced factor (DIF) as a potential molecular link between the activities of IFN-gamma and of growth and differentiation factors. DIF DNA binding was activated by colony-stimulating factor 1 in murine macrophages and also during tetradecanoyl phorbol acetate-induced differentiation or IFN-gamma treatment in myeloid U937 cells. IFN-gamma activation of DIF decreased significantly upon monocytic differentiation. DIF binding to DNA was inhibited by antiphosphotyrosine antibodies and could be induced by treatment of U937 cells with vanadate. Unlike GAF, DIF-DNA complexes did not contain the 91-kDa protein (p91) from ISGF-3. DIF bound with high affinity to GAS from the promoters of the IFP 53/tryptophanyl-tRNA synthetase and Fc gamma RI genes, intermediate affinity to the Ly6A/E GAS, and low affinity to the guanylate-binding protein GAS. DIF may belong to a family of cytokine- or growth factor-induced factors binding with variable affinities to GAS-related elements: the interleukin-6-responsive acute-phase response factor associated with GAS from different IFN-inducible promoters but with a different preference of binding compared with DIF. The sis-inducible element of the c-fos promoter bound GAF but not DIF. However, the sis-inducible element could be changed by point mutation to compete for GAF and DIF binding. Our data show DIF to be a novel DNA-binding protein which is activated in response to differentiating signals. Moreover, they suggest that a family of cytokine- or growth factor-regulated proteins integrates and coordinates the responses to cytokines and to growth and differentiation factors by binding to GAS-related elements.

Animals↗
PubMed1994

The signalling pathways of interleukin-6 and gamma interferon converge by the activation of different transcription factors which bind to common responsive DNA elements.

Interleukin-6 (IL-6) and gamma interferon (IFN-gamma) induce a partially overlapping set of genes, including the genes for interferon regulatory factor 1 (IRF-1), intercellular adhesion molecule 1 (ICAM-1), and the acute-phase protein alpha 2-macroglobulin. We report here that the rat alpha 2-macroglobulin promoter is activated by IFN-gamma in human hepatoma (HepG2) cells and that the IFN-gamma response element maps to the same site previously defined as the acute-phase response element (APRE), which binds the IL-6-activated transcription factor APRF (acute-phase response factor). As was reported for fibroblasts, the IFN-gamma-regulated transcription factor GAF is phosphorylated at tyrosine after IFN-gamma treatment of HepG2 cells. IFN-gamma posttranslationally activates a protein which specifically binds to the alpha 2-macroglobulin APRE. This protein is shown to be identical or closely related to GAF. Although APRF and GAF are shown to represent different proteins, their binding sequence specificities are very similar. APRF and GAF bind equally well to the APRE sequences of various acute-phase protein genes as well as to the IFN-gamma response elements of the IRF-1, ICAM-1, and other IFN-gamma-inducible genes. Transient transfection analysis revealed that the IFN-gamma response elements of the IRF-1 and ICAM-1 promoters are able to confer responsiveness to both IFN-gamma and IL-6 onto a heterologous promoter. Therefore, APRF and GAF are likely to be involved in the transcriptional induction of these immediate-early genes by IL-6 and IFN-gamma, respectively. Taken together, these results demonstrate that two functionally distinct hormones, IL-6 and IFN-gamma, act through common regulatory elements to which different transcription factors sharing almost the same sequence specificity bind.

Alkaloids↗