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1.
Proc Natl Acad Sci U S A ; 121(15): e2320456121, 2024 Apr 09.
Article in English | MEDLINE | ID: mdl-38568974

ABSTRACT

Prion-like spread of disease-specific tau conformers is a hallmark of all tauopathies. A 19-residue probe peptide containing a P301L mutation and spanning the R2/R3 splice junction of tau folds and stacks into seeding-competent fibrils and induces aggregation of 4R, but not 3R tau. These tau peptide fibrils propagate aggregated intracellular tau over multiple generations, have a high ß-sheet content, a colocalized lipid signal, and adopt a well-defined U-shaped fold found in 4R tauopathy brain-derived fibrils. Fully atomistic replica exchange molecular dynamics (MD) simulations were used to compute the free energy landscapes of the conformational ensemble of the peptide monomers. These identified an aggregation-prohibiting ß-hairpin structure and an aggregation-competent U-fold unique to 4R tauopathy fibrils. Guided by MD simulations, we identified that the N-terminal-flanking residues to PHF6, which slightly vary between 4R and 3R isoforms, modulate seeding. Strikingly, when a single amino acid switch at position 305 replaced the serine of 4R tau with a lysine from the corresponding position in the first repeat of 3R tau, the seeding induced by the 19-residue peptide was markedly reduced. Conversely, a 4R tau mimic with three repeats, prepared by replacing those amino acids in the first repeat with those amino acids uniquely present in the second repeat, recovered aggregation when exposed to the 19-residue peptide. These peptide fibrils function as partial prions to recruit naive 4R tau-ten times the length of the peptide-and serve as a critical template for 4R tauopathy propagation. These results hint at opportunities for tau isoform-specific therapeutic interventions.


Subject(s)
Prions , Tauopathies , Humans , tau Proteins/metabolism , Tauopathies/metabolism , Protein Isoforms/metabolism , Prions/metabolism , Peptides , Amino Acids
2.
bioRxiv ; 2023 Nov 28.
Article in English | MEDLINE | ID: mdl-37693456

ABSTRACT

Prion-like spread of disease-specific tau conformers is a hallmark of all tauopathies. A 19-residue probe peptide containing a P301L mutation and spanning the R2/R3 splice junction of tau, folds and stacks into seeding-competent fibrils and induces aggregation of 4R, but not 3R tau. These tau peptide fibrils propagate aggregated intracellular tau over multiple generations, have a high ß-sheet content, a colocalized lipid signal, and adopt a well-defined U-shaped fold found in 4R tauopathy brain-derived fibrils. Fully atomistic replica exchange molecular dynamics (MD) simulations were used to compute the free energy landscapes of the conformational ensemble of the peptide monomers. These identified an aggregation-prohibiting ß-hairpin structure and an aggregation-competent U-fold unique to 4R tauopathy fibrils. Guided by MD simulations, we identified that the N-terminal-flanking residues to PHF6, which slightly vary between 4R and 3R isoforms, modulate seeding. Strikingly, when a single amino acid switch at position 305 replaced the serine of 4R tau with a lysine from the corresponding position in the first repeat of 3R tau, the seeding induced by the 19-residue peptide was markedly reduced. Conversely, a 4R tau mimic with three repeats, prepared by replacing those amino acids in the first repeat with those amino acids uniquely present in the second repeat, recovered aggregation when exposed to the 19-residue peptide. These peptide fibrils function as partial prions to recruit naïve 4R tau-ten times the length of the peptide-and serve as a critical template for 4R tauopathy propagation. These results hint at opportunities for tau isoform-specific therapeutic interventions.

3.
Mol Oncol ; 17(2): 230-237, 2023 02.
Article in English | MEDLINE | ID: mdl-36269676

ABSTRACT

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) account for ≤ 12% of all EGFR-mutant nonsmall cell lung cancers. We analysed real-world datasets to determine the frequency of ex20ins variants, and the ability of polymerase chain reaction (PCR) and next-generation sequencing (NGS) to identify them. Three real-world United States NGS databases were used: GENIE, FoundationInsights, and GuardantINFORM. Mutation profiles consistent with in-frame EGFR ex20ins were summarized. GENIE, FoundationInsights, and GuardantINFORM datasets identified 180, 627, and 627 patients with EGFR ex20ins respectively. The most frequent insertion region of exon 20 was the near loop (~ 70%), followed by the far loop (~ 30%) and the helical (~ 3-6%) regions. GENIE, FoundationInsights, and GuardantINFORM datasets identified 41, 102, and 96 unique variants respectively. An analysis of variants projected that ~ 50% of EGFR ex20ins identified by NGS would have been missed by PCR-based assays. Given the breadth of EGFR ex20ins identified in the real-world US datasets, the ability of PCR to identify these mutations is limited. NGS platforms are more appropriate to identify patients likely to benefit from EGFR ex20ins-targeted therapies.


Subject(s)
Lung Neoplasms , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Mutagenesis, Insertional/genetics , ErbB Receptors/genetics , Mutation/genetics , Exons/genetics , Genomics , Protein Kinase Inhibitors
4.
Toxicol Appl Pharmacol ; 285(1): 51-60, 2015 May 15.
Article in English | MEDLINE | ID: mdl-25841593

ABSTRACT

Safety pharmacology studies that evaluate new drug entities for potential cardiac liability remain a critical component of drug development. Current studies have shown that in vitro tests utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) may be beneficial for preclinical risk evaluation. We recently demonstrated that an in vitro multi-parameter test panel assessing overall cardiac health and function could accurately reflect the associated clinical cardiotoxicity of 4 FDA-approved targeted oncology agents using hiPS-CM. The present studies expand upon this initial observation to assess whether this in vitro screen could detect cardiotoxicity across multiple drug classes with known clinical cardiac risks. Thus, 24 drugs were examined for their effect on both structural (viability, reactive oxygen species generation, lipid formation, troponin secretion) and functional (beating activity) endpoints in hiPS-CM. Using this screen, the cardiac-safe drugs showed no effects on any of the tests in our panel. However, 16 of 18 compounds with known clinical cardiac risk showed drug-induced changes in hiPS-CM by at least one method. Moreover, when taking into account the Cmax values, these 16 compounds could be further classified depending on whether the effects were structural, functional, or both. Overall, the most sensitive test assessed cardiac beating using the xCELLigence platform (88.9%) while the structural endpoints provided additional insight into the mechanism of cardiotoxicity for several drugs. These studies show that a multi-parameter approach examining both cardiac cell health and function in hiPS-CM provides a comprehensive and robust assessment that can aid in the determination of potential cardiac liability.


Subject(s)
Antineoplastic Agents/pharmacology , Heart Diseases/chemically induced , High-Throughput Screening Assays , Induced Pluripotent Stem Cells/drug effects , Myocytes, Cardiac/drug effects , Toxicity Tests/methods , Antineoplastic Agents/classification , Biomarkers/metabolism , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Heart Diseases/metabolism , Heart Diseases/pathology , Humans , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/pathology , Lipid Metabolism/drug effects , Molecular Structure , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Reproducibility of Results , Risk Assessment , Structure-Activity Relationship , Time Factors , Troponin I/metabolism
5.
Toxicol Sci ; 143(1): 147-55, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25304212

ABSTRACT

Ponatinib, a multi-targeted TKI and potent pan-ABL inhibitor, approved for the treatment of Ph + ALL and CML, was temporarily withdrawn from the U.S. market due to severe vascular adverse events. Cardiac-specific toxicities including myocardial infarction, severe congestive heart failure, and cardiac arrhythmias have also been shown with ponatinib. Targeted oncology agents such as ponatinib have transformed cancer treatment but often induce toxicity due to inhibition of survival pathways shared by both cancer and cardiac cells. These toxicities are often missed by the standard preclinical toxicity assessment methods, which include human Ether-à-go-go-related gene (hERG) and animal toxicity testing. In this study, we show that a multiparameter in vitro toxicity screening approach using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) accurately predicted the cardiac toxicity potential of ponatinib. This in vitro model evaluated ponatinib's effect on the overall cell health, mitochondrial stress, and function of hiPSC-CM and also provided mechanistic insight into the signaling pathways and cellular structures altered with treatment. We show here that ponatinib rapidly inhibits prosurvival signaling pathways, induces structural cardiac toxicity (as shown by actin cytoskeleton damage, mitochondrial stress, cell death, and troponin secretion), and disrupts cardiac cell beating. Most of these effects occurred at doses between 10× and 50× ponatinib's Cmax, a dose range shown to be relevant for accurate prediction of in vivo toxicity. Together these studies show that a comprehensive in vitro screening tool in a more relevant human cardiac cell model can improve the detection of cardiac toxicity with targeted oncology agents such as ponatinib.


Subject(s)
Antineoplastic Agents/toxicity , Cell Differentiation , Heart Diseases/chemically induced , Imidazoles/toxicity , Induced Pluripotent Stem Cells/drug effects , Myocytes, Cardiac/drug effects , Protein Kinase Inhibitors/toxicity , Pyridazines/toxicity , Toxicity Tests/methods , Actin Cytoskeleton/drug effects , Actin Cytoskeleton/metabolism , Actin Cytoskeleton/pathology , Cell Death/drug effects , Cell Line , Dose-Response Relationship, Drug , Heart Diseases/metabolism , Heart Diseases/pathology , Heart Diseases/physiopathology , Heart Rate/drug effects , Humans , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/pathology , Mitochondria, Heart/drug effects , Mitochondria, Heart/metabolism , Mitochondria, Heart/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Oxidative Stress/drug effects , Risk Assessment , Signal Transduction/drug effects , Time Factors , Troponin/metabolism
6.
Toxicol Appl Pharmacol ; 272(1): 245-55, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-23707608

ABSTRACT

Tyrosine kinase inhibitors (TKi) have greatly improved the treatment and prognosis of multiple cancer types. However, unexpected cardiotoxicity has arisen in a subset of patients treated with these agents that was not wholly predicted by pre-clinical testing, which centers around animal toxicity studies and inhibition of the human Ether-à-go-go-Related Gene (hERG) channel. Therefore, we sought to determine whether a multi-parameter test panel assessing the effect of drug treatment on cellular, molecular, and electrophysiological endpoints could accurately predict cardiotoxicity. We examined how 4 FDA-approved TKi agents impacted cell viability, apoptosis, reactive oxygen species (ROS) generation, metabolic status, impedance, and ion channel function in human cardiomyocytes. The 3 drugs clinically associated with severe cardiac adverse events (crizotinib, sunitinib, nilotinib) all proved to be cardiotoxic in our in vitro tests while the relatively cardiac-safe drug erlotinib showed only minor changes in cardiac cell health. Crizotinib, an ALK/MET inhibitor, led to increased ROS production, caspase activation, cholesterol accumulation, disruption in cardiac cell beat rate, and blockage of ion channels. The multi-targeted TKi sunitinib showed decreased cardiomyocyte viability, AMPK inhibition, increased lipid accumulation, disrupted beat pattern, and hERG block. Nilotinib, a second generation Bcr-Abl inhibitor, led to increased ROS generation, caspase activation, hERG block, and an arrhythmic beat pattern. Thus, each drug showed a unique toxicity profile that may reflect the multiple mechanisms leading to cardiotoxicity. This study demonstrates that a multi-parameter approach can provide a robust characterization of drug-induced cardiomyocyte damage that can be leveraged to improve drug safety during early phase development.


Subject(s)
Myocytes, Cardiac/drug effects , Protein Kinase Inhibitors/toxicity , Protein-Tyrosine Kinases/antagonists & inhibitors , Caspase 3/metabolism , Caspase 7/metabolism , Cell Survival/drug effects , Cells, Cultured , Cholesterol/metabolism , Crizotinib , ERG1 Potassium Channel , Enzyme Activation/drug effects , Erlotinib Hydrochloride , Ether-A-Go-Go Potassium Channels/biosynthesis , Ether-A-Go-Go Potassium Channels/genetics , Humans , Indoles/toxicity , Ion Channels/drug effects , Lipids/biosynthesis , Myocytes, Cardiac/ultrastructure , Patch-Clamp Techniques , Pluripotent Stem Cells/drug effects , Pyrazoles/toxicity , Pyridines/toxicity , Pyrimidines/toxicity , Pyrroles/toxicity , Quinazolines/toxicity , RNA/biosynthesis , RNA/isolation & purification , Reactive Oxygen Species/metabolism , Real-Time Polymerase Chain Reaction , Sunitinib
7.
Cell Cycle ; 7(12): 1769-75, 2008 Jun 15.
Article in English | MEDLINE | ID: mdl-18594201

ABSTRACT

ErbB2 targeted therapies represent an attractive strategy in breast cancer. Herceptin, an anti-ErbB2 monoclonal antibody, is an approved treatment for patients with ErbB2-overexpressing breast cancers. ErbB2 signaling can also be blocked using small molecule tyrosine kinase inhibitors, like Lapatinib, that compete with ATP for binding at the ErbB2 catalytic kinase domain. The principal adverse event attributable to Herceptin is cardiac toxicity. Data from clinical trials show that, unlike Herceptin, Lapatinib may have reduced cardiac toxicity. This study was conducted to elucidate pathways which may contribute to cardiac toxicity or survival using Lapatinib and Herceptin. Our results show that treatments directed to ErbB1/2 receptors using GW-2974 (a generic ErbB1/2 inhibitor) activated AMPK, a key regulator in mitochondrial energy production pathways in human cardiac cells and cancer cells. Although Herceptin downregulates tumor survival pathways, AMPK fails to be activated in tumor and cardiac cells. When treated in combination with TNFalpha, a known cytokine associated with cardiac toxicity, GW-2974 protected cardiac cells from cell death whereas Herceptin contributed to TNFalpha-induced cellular killing. Since activity of AMPK in cardiac cells is associated with stress induced survival in response to cytokines or energy depletion, cardiac toxicity by Herceptin may be a consequence of failure to induce stress-related survival mechanisms. Thus, the ability to activate AMPK after treatment with tyrosine kinase inhibitors may be a crucial factor for increased efficacy against the tumor and decreased risk of cardiomyopathy.


Subject(s)
Antineoplastic Agents/toxicity , Multienzyme Complexes/metabolism , Myocytes, Cardiac/drug effects , Protein Kinase Inhibitors/toxicity , Protein Serine-Threonine Kinases/metabolism , Quinazolines/toxicity , AMP-Activated Protein Kinases , Antibodies, Monoclonal/toxicity , Antibodies, Monoclonal, Humanized , Cell Line, Tumor , Cells, Cultured , Enzyme Activation , ErbB Receptors/antagonists & inhibitors , Genes, p53 , Humans , Mutation , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/metabolism , Neoplasms/enzymology , Neoplasms/genetics , Neoplasms/metabolism , Receptor, ErbB-2/antagonists & inhibitors , Trastuzumab
8.
J Immunol ; 179(11): 7663-73, 2007 Dec 01.
Article in English | MEDLINE | ID: mdl-18025212

ABSTRACT

B cells produce Ig H chain (IgH) mRNA and protein, primarily of the membrane-bound specific form. Plasma cells produce 20- to 50-fold higher amounts of IgH mRNA, most processed to the secretory specific form; this shift is mediated by substantial changes in RNA processing but only a small increase in IgH transcription rate. We investigated RNA polymerase II (RNAP-II) loading and phosphorylation of its C-terminal domain (CTD) on the IgG2a H chain gene, comparing two mouse cell lines representing B (A20) and plasma cells (AxJ) that express the identical H chain gene whose RNA is processed in different ways. Using chromatin immunoprecipitation and real-time PCR, we detected increased RNAP-II and Ser-2 and Ser-5 phosphorylation of RNAP-II CTD close to the IgH promoter in plasma cells. We detected increased association of several 3' end-processing factors, ELL2 and PC4, at the 5' end of the IgH gene in AxJ as compared with A20 cells. Polymerase progress and factor associations were inhibited by 5,6-dichlorobenzimidazole riboside, a drug that interferes with the addition of the Ser-2 to the CTD of RNAP-II. Taken together, these data indicate a role for CTD phosphorylation and polyadenylation/ELL2/PC4 factor loading on the polymerase in the choice of the secretory poly(A) site for the IgH gene.


Subject(s)
Immunoglobulin Heavy Chains/immunology , Plasma Cells/immunology , RNA Polymerase II/immunology , RNA, Messenger/immunology , Serine/metabolism , Transcription, Genetic/genetics , Animals , B-Lymphocytes/immunology , Base Sequence , Cell Line , Cells, Cultured , Chromatin Immunoprecipitation/methods , Immunoglobulin Heavy Chains/genetics , Mice , Molecular Sequence Data , Phosphorylation , Polyadenylation/immunology , Protein Structure, Tertiary , RNA Polymerase II/metabolism , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Serine/immunology , Transcription, Genetic/immunology
9.
Cell Cycle ; 6(21): 2585-90, 2007 Nov 01.
Article in English | MEDLINE | ID: mdl-17957144

ABSTRACT

The microRNA let-7 regulates late embryonic development by suppressing expression of a number of genes such as c-myc and RAS as well as the embryonic gene high mobility group, A2 (HMGA2). We now demonstrate that HMGA2 is more efficiently targeted by let-7 than RAS. Its expression inversely correlates with the expression of let-7 in the NCI60 cells lines, and the expression of RAS does not change when amounts of let-7 that efficiently silence expression of HMGA2 are introduced into tumor cells. We did not find a difference in the expression of HMGA2 between primary ovarian cancer samples and matching metastases, suggesting that the expression of HMGA2 represents an early event during cancer progression. The late repression of HMGA2 by let-7 during embryonic development, and the early reexpression of HMGA2 during cancer development, is in line with the hypothesis that cancer development represents a case of reverse embryogenesis.


Subject(s)
Gene Expression Regulation, Neoplastic/physiology , HMGA2 Protein/antagonists & inhibitors , HMGA2 Protein/biosynthesis , MicroRNAs/physiology , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/prevention & control , Cell Line, Tumor , Disease Progression , Female , HMGA2 Protein/genetics , Humans , Ovarian Neoplasms/genetics , Suppression, Genetic
10.
Proc Natl Acad Sci U S A ; 104(27): 11400-5, 2007 Jul 03.
Article in English | MEDLINE | ID: mdl-17600087

ABSTRACT

The early phases of carcinogenesis resemble embryonic development, often involving the reexpression of embryonic mesenchymal genes. The NCI60 panel of human tumor cell lines can genetically be subdivided into two superclusters (SCs) that correspond to CD95 Type I and II cells. SC1 cells are characterized by a mesenchymal and SC2 cells by an epithelial gene signature, suggesting that SC1 cells represent less differentiated, advanced stages of cancer. miRNAs are small 20- to 22-nucleotide-long noncoding RNAs that inhibit gene expression at the posttranscriptional level. By performing miRNA expression analysis on 10 Type I and 10 Type II cells, we have determined that SC1 cells express low and SC2 cells high levels of the miRNA let-7, respectively, suggesting that let-7 is a marker for less advanced cancers. Expression of the let-7 target high-mobility group A2 (HMGA2), an early embryonic gene, but not of classical epithelial or mesenchymal markers such as E-cadherin or vimentin, inversely correlated with let-7 expression in SC1 and SC2 cells. Using ovarian cancer as a model, we demonstrate that expression of let-7 and HMGA2 is a better predictor of prognosis than classical markers such as E-cadherin, vimentin, and Snail. These data identify loss of let-7 expression as a marker for less differentiated cancer.


Subject(s)
Biomarkers, Tumor/biosynthesis , Biomarkers, Tumor/genetics , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Gene Expression Regulation, Neoplastic , MicroRNAs/biosynthesis , MicroRNAs/genetics , Ovarian Neoplasms/pathology , Biomarkers, Tumor/physiology , Cell Differentiation/genetics , Cell Line , Cell Line, Tumor , Disease Progression , Female , HMGA2 Protein/biosynthesis , HMGA2 Protein/genetics , HeLa Cells , Humans , MicroRNAs/physiology , Ovarian Neoplasms/genetics , Predictive Value of Tests
11.
J Biol Chem ; 280(48): 39950-61, 2005 Dec 02.
Article in English | MEDLINE | ID: mdl-16207706

ABSTRACT

Lipopolysaccharide (LPS) activation of murine RAW 264.7 macrophages influences the expression of multiple genes through transcriptional and post-transcriptional mechanisms. We observed a 5-fold increase in CstF-64 expression following LPS treatment of RAW macrophages. The increase in CstF-64 protein was specific in that several other factors involved in 3'-end processing were not affected by LPS stimulation. Activation of RAW macrophages with LPS caused an increase in proximal poly(A) site selection within a reporter mini-gene containing two linked poly(A) sites that occurred concomitant with the increase in CstF-64 expression. Furthermore, forced overexpression of the CstF-64 protein also induced alternative poly(A) site selection on the reporter minigene. Microarray analysis performed on CstF-64 overexpressing RAW macrophages revealed that elevated levels of CstF-64 altered the expression of 51 genes, 14 of which showed similar changes in gene expression with LPS stimulation. Sequence analysis of the 3'-untranslated regions of these 51 genes revealed that over 45% possess multiple putative poly(A) sites. Two of these 51 genes demonstrated alternative polyadenylation under both LPS-stimulating and CstF-64-overexpressing conditions. We concluded that the physiologically increased levels of CstF-64 observed in LPS-stimulated RAW macrophages contribute to the changes in expression and alternative polyadenylation of a number of genes, thus identifying another level of gene regulation that occurs in macrophages activated with LPS.


Subject(s)
Cleavage Stimulation Factor/chemistry , Cleavage Stimulation Factor/physiology , Gene Expression Regulation , Lipopolysaccharides/metabolism , Macrophages/metabolism , Poly A/chemistry , 3' Untranslated Regions , Algorithms , Animals , Binding Sites , Blotting, Western , Cell Proliferation , Cells, Cultured , Genes, Reporter , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred C57BL , Models, Biological , Models, Genetic , Models, Statistical , Oligonucleotide Array Sequence Analysis , Oligonucleotides/chemistry , Open Reading Frames , Polyadenylation , Promoter Regions, Genetic , Protein Binding , Protein Conformation , RNA/chemistry , RNA Processing, Post-Transcriptional , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Transcription, Genetic
12.
Biol Reprod ; 66(3): 659-66, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11870072

ABSTRACT

In the mammalian testis, the binding of FSH to Sertoli cells activates the cAMP-dependent protein kinase A signaling pathway, resulting in the phosphorylation of the cAMP response element binding protein (CREB). Previous studies have also shown that CREB gene expression is activated by cAMP in Sertoli cells and that 2 cAMP response elements (CREs) that bind CREB and a neighboring Sp1 binding site are required for basal and cAMP-inducible CREB promoter activity. In contrast, CREB expression has been less well characterized in testis germ cells. We demonstrated that CREB and Sp1 are expressed in early germ cells only through the midpachytene stage of spermatogenesis. Furthermore, CREB promoter activity was induced over 70-fold by transient overexpression of Sp1 in SL2 cells, suggesting that Sp1 is an important regulator of CREB expression. Further studies of the CREB promoter revealed an additional regulatory element in the -130 region between the Sp1 and CREB transcription factor binding sites that is necessary for full promoter activity. Proteins expressed in Sertoli cells and germ cells bind specifically to the newly identified regulatory region. These studies suggest that proteins binding to Sp1 motifs and the -130 region are required to activate the CREB promoter.


Subject(s)
Cyclic AMP Response Element-Binding Protein/genetics , Gene Expression Regulation/drug effects , Sp1 Transcription Factor/pharmacology , Testis/metabolism , Animals , Binding Sites , DNA/chemistry , DNA/metabolism , Drosophila/metabolism , Gene Expression , Glutathione Transferase , Male , Nuclear Proteins/metabolism , Promoter Regions, Genetic , Rats , Regulatory Sequences, Nucleic Acid , Sertoli Cells/metabolism , Sp1 Transcription Factor/genetics , Spermatogenesis , Spermatozoa/metabolism , Transfection
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