early growth response transcription factors


Summary: A family of transcription factors that are induced by GROWTH FACTORS and contain a highly conserved DNA-binding domain composed of three ZINC FINGER MOTIFS.

Top Publications

  1. Venuprasad K, Huang H, Harada Y, Elly C, Subramaniam M, Spelsberg T, et al. The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1. Nat Immunol. 2008;9:245-53 pubmed publisher
    ..These results suggest TIEG and Itch contribute to a ubiquitin-dependent nonproteolytic pathway that regulates inducible Foxp3 expression and the control of allergic responses. ..
  2. Jin W, Di G, Li J, Chen Y, Li W, Wu J, et al. TIEG1 induces apoptosis through mitochondrial apoptotic pathway and promotes apoptosis induced by homoharringtonine and velcade. FEBS Lett. 2007;581:3826-32 pubmed
    ..We concluded that TIEG1 is a key regulator which induces and promotes apoptosis through the mitochondrial apoptotic pathway. ..
  3. Johnsen S, Subramaniam M, Janknecht R, Spelsberg T. TGFbeta inducible early gene enhances TGFbeta/Smad-dependent transcriptional responses. Oncogene. 2002;21:5783-90 pubmed
    ..In conclusion, these results describe a novel mechanism for the potentiation of TGFbeta/Smad signaling via repression of the inhibitory Smad7 gene by TIEG. ..
  4. Benos P, Lapedes A, Stormo G. Probabilistic code for DNA recognition by proteins of the EGR family. J Mol Biol. 2002;323:701-27 pubmed
    ..We also employ the assumption that the total binding energy is the sum of the energies of the individual contacts, but we describe how that assumption can be relaxed at the cost of additional parameters. ..
  5. Hawse J, Subramaniam M, Monroe D, Hemmingsen A, Ingle J, Khosla S, et al. Estrogen receptor beta isoform-specific induction of transforming growth factor beta-inducible early gene-1 in human osteoblast cells: an essential role for the activation function 1 domain. Mol Endocrinol. 2008;22:1579-95 pubmed publisher
  6. Bhattacharyya S, Wu M, Fang F, Tourtellotte W, Feghali Bostwick C, Varga J. Early growth response transcription factors: key mediators of fibrosis and novel targets for anti-fibrotic therapy. Matrix Biol. 2011;30:235-42 pubmed publisher
    ..As a novel profibrotic mediator, Egr-1 thus appears to be a promising potential target for the development of anti-fibrotic therapies. ..
  7. Ludwig A, Uvarov P, Soni S, Thomas Crusells J, Airaksinen M, Rivera C. Early growth response 4 mediates BDNF induction of potassium chloride cotransporter 2 transcription. J Neurosci. 2011;31:644-9 pubmed publisher
    ..These results indicate that Egr4 is an important component in the mechanism of BDNF-dependent KCC2 gene regulation via the ERK1/2 pathway in immature neurons. ..
  8. Ribeiro A, Bronk S, Roberts P, Urrutia R, Gores G. The transforming growth factor beta(1)-inducible transcription factor TIEG1, mediates apoptosis through oxidative stress. Hepatology. 1999;30:1490-7 pubmed
    ..The antioxidant, trolox, decreased the formation of reactive oxygen species and apoptosis. These results demonstrate that similar to TGF-beta(1), TIEG1 induces apoptosis by a mechanism involving the formation of reactive oxygen species. ..
  9. Hefferan T, Reinholz G, Rickard D, Johnsen S, Waters K, Subramaniam M, et al. Overexpression of a nuclear protein, TIEG, mimics transforming growth factor-beta action in human osteoblast cells. J Biol Chem. 2000;275:20255-9 pubmed
    ..TGF-beta treatment of the overexpressed cells showed no added effects. These findings and other published reports support a primary role of TIEG as a transcription factor in the TGF-beta signaling pathway. ..

More Information


  1. Hadziselimovic F, Hadziselimovic N, Demougin P, Krey G, Hoecht B, Oakeley E. EGR4 is a master gene responsible for fertility in cryptorchidism. Sex Dev. 2009;3:253-63 pubmed publisher
    ..Thus, we found multiple differences in gene expression between the high and low infertility risk groups, confirming the importance of an intact hypothalamo-pituitary testicular axis and EGR4 in fertility development. ..
  2. Uvarov P, Ludwig A, Markkanen M, Rivera C, Airaksinen M. Upregulation of the neuron-specific K+/Cl- cotransporter expression by transcription factor early growth response 4. J Neurosci. 2006;26:13463-73 pubmed
    ..Together, the results indicate an important role for Egr4 in the developmental upregulation of KCC2 gene expression. ..
  3. Gómez Martín D, Díaz Zamudio M, Galindo Campos M, Alcocer Varela J. Early growth response transcription factors and the modulation of immune response: implications towards autoimmunity. Autoimmun Rev. 2010;9:454-8 pubmed publisher
    ..The deficiency of these transcription factors has been associated to deficient Cbl-b expression, a resistant to anergy phenotype, and expansion of effector and activated T cells. ..
  4. Reinholz M, An M, Johnsen S, Subramaniam M, Suman V, Ingle J, et al. Differential gene expression of TGF beta inducible early gene (TIEG), Smad7, Smad2 and Bard1 in normal and malignant breast tissue. Breast Cancer Res Treat. 2004;86:75-88 pubmed
    ..Further investigation is necessary to validate the ability of these genes to discriminate between different populations of breast cancer patients. ..
  5. Subramaniam M, Hefferan T, Tau K, Peus D, Pittelkow M, Jalal S, et al. Tissue, cell type, and breast cancer stage-specific expression of a TGF-beta inducible early transcription factor gene. J Cell Biochem. 1998;68:226-36 pubmed
    ..2, and past studies with pancreatic carcinoma, suggests that TIEG may play a role in tumor suppressor gene activities, apoptosis, or some other regulatory function of cell cycle regulation. ..
  6. Liu J, Stormo G. Quantitative analysis of EGR proteins binding to DNA: assessing additivity in both the binding site and the protein. BMC Bioinformatics. 2005;6:176 pubmed
    ..A simple modification to the independent model provides a better fit to the complete data. ..
  7. Chrisman H, Tindall D. Identification and characterization of a consensus DNA binding element for the zinc finger transcription factor TIEG/EGRalpha. DNA Cell Biol. 2003;22:187-99 pubmed
    ..Mutational analysis of the binding site identified a GT-rich core (5'-GGTGTG-3') that was necessary for binding, with mutations outside of this region causing only a small to moderate decrease in binding. ..
  8. Johnsen S, Subramaniam M, Monroe D, Janknecht R, Spelsberg T. Modulation of transforming growth factor beta (TGFbeta)/Smad transcriptional responses through targeted degradation of TGFbeta-inducible early gene-1 by human seven in absentia homologue. J Biol Chem. 2002;277:30754-9 pubmed
    ..In this manner, turnover of TIEG1 may serve to limit the duration and/or magnitude of TGFbeta responses. ..
  9. Hogarth C, Mitchell D, Small C, Griswold M. EGR4 displays both a cell- and intracellular-specific localization pattern in the developing murine testis. Dev Dyn. 2010;239:3106-14 pubmed publisher
    ..Taken together, these data suggest that Egr4 may regulate spermatogenesis at multiple steps, with roles in the dividing Sertoli cells, peritubular myoid cells, and the meiotic and elongating haploid germ cell populations. ..
  10. Hefferan T, Subramaniam M, Khosla S, Riggs B, Spelsberg T. Cytokine-specific induction of the TGF-beta inducible early gene (TIEG): regulation by specific members of the TGF-beta family. J Cell Biochem. 2000;78:380-90 pubmed
    ..In summary, the relative potencies of these TGF-beta family members to induce TIEG expression generally follows the general osteoinductive capacity of these cytokines, with TGF-beta > BMP-2 > BMP-4 > activin > BMP-6. ..
  11. Tachibana I, Imoto M, Adjei P, Gores G, Subramaniam M, Spelsberg T, et al. Overexpression of the TGFbeta-regulated zinc finger encoding gene, TIEG, induces apoptosis in pancreatic epithelial cells. J Clin Invest. 1997;99:2365-74 pubmed
    ..Together, these results support a role for TIEG in linking TGFbeta-mediated signaling cascades to the regulation of pancreatic epithelial cell growth. ..
  12. Hernandez J, Cooper J, Babel N, Morton C, Rosemurgy A. TNFalpha gene delivery therapy for solid tumors. Expert Opin Biol Ther. 2010;10:993-9 pubmed publisher
    ..The completion of several ongoing randomized trials will help to better define the role for TNFalpha gene delivery therapy in the treatment of solid tumors. ..
  13. Ma J, Ning Y, Xu M, Hou Y, Wang N, Hou X, et al. Thalidomide corrects impaired mesenchymal stem cell function in inducing tolerogenic DCs in patients with immune thrombocytopenia. Blood. 2013;122:2074-82 pubmed publisher
    ..THD could restore the regulatory effect of MSCs on DCs. These findings will help us understand the pathogenesis of ITP, and with appropriate safeguards, THD may benefit patients with ITP. ..
  14. Deneault E, Wilhelm B, Bergeron A, Barabé F, Sauvageau G. Identification of non-cell-autonomous networks from engineered feeder cells that enhance murine hematopoietic stem cell activity. Exp Hematol. 2013;41:470-478.e4 pubmed publisher
    ..This last finding further supports a lack of conservation in determinants that control HSC self-renewal in mouse versus human cells. ..
  15. Kawamura S, Sato I, Wada T, Yamaguchi K, Li Y, Li D, et al. Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling. Cell Death Differ. 2012;19:170-9 pubmed publisher
    ..These data suggest that NEU3 regulates tumor progression through AR signaling, and thus be a potential tool for diagnosis and therapy of androgen-independent prostate cancer. ..
  16. To S, Simpson E, Knower K, Clyne C. Involvement of early growth response factors in TNF?-induced aromatase expression in breast adipose. Breast Cancer Res Treat. 2013;138:193-203 pubmed publisher
    ..4-derived CYP19A1 transcription in BAFs. These studies unveil a novel component of the aromatase gene regulatory network and further enhance the complexity of oestrogen production in the breast. ..
  17. Gallitano A, Tillman R, Dinu V, Geller B. Family-based association study of early growth response gene 3 with child bipolar I disorder. J Affect Disord. 2012;138:387-96 pubmed publisher
    ..Such studies may help reveal mechanisms by which environment can interact with genetic predisposition to influence this severe mental illness. ..
  18. Subramaniam M, Hawse J, Rajamannan N, Ingle J, Spelsberg T. Functional role of KLF10 in multiple disease processes. Biofactors. 2010;36:8-18 pubmed publisher
  19. Kim J, Shin S, Subramaniam M, Bruinsma E, Kim T, Hawse J, et al. Histone demethylase JARID1B/KDM5B is a corepressor of TIEG1/KLF10. Biochem Biophys Res Commun. 2010;401:412-6 pubmed publisher
  20. Yan X, Jin S, Li S, Gong F, Zhang D, Zhang X, et al. Heparanase modulation of early growth response gene expression. Zoolog Sci. 2011;28:189-94 pubmed publisher
    ..Furthermore, overexpression of heparanase influenced expression of most genes involved in heparan sulfate proteoglycan biosynthesis, albeit to a different degree in the cortex and thalamus of the transgenic mice. ..
  21. Bos J, Subramaniam M, Hawse J, Christiaans I, Rajamannan N, Maleszewski J, et al. TGF?-inducible early gene-1 (TIEG1) mutations in hypertrophic cardiomyopathy. J Cell Biochem. 2012;113:1896-903 pubmed publisher
    ..Functional assays suggest a role for PTTG1 in the pathogenesis of TIEG1-mediated HCM. Up-regulation of PTTG1 seems to be a common pathway in hypertrophic heart disease, including TIEG1-mediated HCM. ..
  22. Gutierrez Aguilar R, Benmezroua Y, Balkau B, Marre M, Helbecque N, Charpentier G, et al. Minor contribution of SMAD7 and KLF10 variants to genetic susceptibility of type 2 diabetes. Diabetes Metab. 2007;33:372-8 pubmed
    ..Although the observed association of SMAD7 and KLF10 gene variants with T2D is modest, they may weakly contribute to a particular genetic background that increases the susceptibility to development of T2D. ..
  23. Chang V, Chu P, Peng S, Mao T, Shan Y, Hsu C, et al. Krüppel-like factor 10 expression as a prognostic indicator for pancreatic adenocarcinoma. Am J Pathol. 2012;181:423-30 pubmed publisher
    ..Our results suggest that KLF10 is a potential clinical predictor for progression of pancreatic cancer. ..
  24. Yao K, Yang Y, Hu R, Miao M, Liao A, Yang W, et al. [Influence of TIEG1 on apoptosis of HL-60 cells and expression of Bcl-2/Bax]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2013;21:587-90 pubmed publisher
    ..During the course of HL-60 cells apoptosis induced by TIEG1, Bcl-2/Bax are associated with HL-60 cell apoptosis induced by TIEG1. ..
  25. Cen M, Hu P, Cai Z, Fang T, Zhang J, Lu M. TIEG1 deficiency confers enhanced myocardial protection in the infarcted heart by mediating the Pten/Akt signalling pathway. Int J Mol Med. 2017;39:569-578 pubmed publisher
    ..On the whole, our findings indicate that the absence of TIEG1 plays a cardioprotective role in ischaemic heart disease by promoting changes in Pten/Akt signalling. ..
  26. Tourtellotte W, Nagarajan R, Bartke A, Milbrandt J. Functional compensation by Egr4 in Egr1-dependent luteinizing hormone regulation and Leydig cell steroidogenesis. Mol Cell Biol. 2000;20:5261-8 pubmed
    ..These results elucidate a novel level of redundancy between Egr4 and Egr1 in regulating LH production in male mice. ..
  27. Tourtellotte W, Nagarajan R, Auyeung A, Mueller C, Milbrandt J. Infertility associated with incomplete spermatogenic arrest and oligozoospermia in Egr4-deficient mice. Development. 1999;126:5061-71 pubmed
    ..These data raise the possibility that Egr4 may contribute to some forms of human idiopathic male infertility. ..
  28. Eid M, Kumar M, Iczkowski K, Bostwick D, Tindall D. Expression of early growth response genes in human prostate cancer. Cancer Res. 1998;58:2461-8 pubmed
    ..These results show that EGR-1 is overexpressed in prostate cancer and suggest a role for EGR-1 in prostate cancer growth. ..
  29. Jin W, Chen B, Li J, Zhu H, Huang M, Gu S, et al. TIEG1 inhibits breast cancer invasion and metastasis by inhibition of epidermal growth factor receptor (EGFR) transcription and the EGFR signaling pathway. Mol Cell Biol. 2012;32:50-63 pubmed publisher
    ..Therefore, TIEG1 is an antimetastasis gene product; regulation of EGFR expression by TIEG1 may be part of an integral signaling pathway that determines and explains breast cancer invasion and metastasis. ..
  30. Ludwig A, Uvarov P, Pellegrino C, Thomas Crusells J, Schuchmann S, Saarma M, et al. Neurturin evokes MAPK-dependent upregulation of Egr4 and KCC2 in developing neurons. Neural Plast. 2011;2011:1-8 pubmed publisher
    ..These results show that Egr4 is an important component in the mechanism for trophic factor-mediated upregulation of KCC2 in immature neurons involving the activation of specific intracellular pathways common to BDNF and Neurturin. ..
  31. Muller I, Rössler O, Wittig C, Menger M, Thiel G. Critical role of Egr transcription factors in regulating insulin biosynthesis, blood glucose homeostasis, and islet size. Endocrinology. 2012;153:3040-53 pubmed publisher
    ..These results show that Egr proteins play an important role in controlling insulin biosynthesis, glucose homeostasis, and islet size of pancreatic ?-cells in vivo...
  32. Ogawa M, Okamura T, Ishikura S, Doi K, Matsuzaki H, Tanaka Y, et al. Zfat-deficiency results in a loss of CD3? phosphorylation with dysregulation of ERK and Egr activities leading to impaired positive selection. PLoS ONE. 2013;8:e76254 pubmed publisher
  33. Hawse J, Cicek M, Grygo S, Bruinsma E, Rajamannan N, Van Wijnen A, et al. TIEG1/KLF10 modulates Runx2 expression and activity in osteoblasts. PLoS ONE. 2011;6:e19429 pubmed publisher
  34. Sung S, Song S, Kang K, Park J, Nam Y, Shin Y, et al. Sequence variations of the EGR4 gene in Korean men with spermatogenesis impairment. BMC Med Genet. 2017;18:47 pubmed publisher
    ..However, our findings did not clearly explain how nonsynonymous EGR4 variations affect spermatogenesis. Therefore, further studies are required to validate the functional impact of EGR4 variations on spermatogenesis. ..
  35. Friedle S, Brautigam V, Nikodemova M, Wright M, Watters J. The P2X7-Egr pathway regulates nucleotide-dependent inflammatory gene expression in microglia. Glia. 2011;59:1-13 pubmed publisher
  36. Barna G, Sebestyen A, Chinopoulos C, Nagy K, Mihalik R, Paku S, et al. TGF beta 1 kills lymphoma cells using mitochondrial apoptotic pathway with the help of caspase-8. Anticancer Res. 2002;22:3867-72 pubmed
    ..There is a time-gat between the early activation of Smad-dependent TIEG and the accumulation of ROS, therefore other participants that start the increase in mitochondrial membrane permeability should be identified. ..
  37. Temiz N, Camacho C. Experimentally based contact energies decode interactions responsible for protein-DNA affinity and the role of molecular waters at the binding interface. Nucleic Acids Res. 2009;37:4076-88 pubmed publisher
    ..Collectively, our method provides the first robust framework to decode the molecular basis of TFs binding to DNA. ..
  38. Jiang L, Chen Y, Chan C, Wang X, Lin L, He M, et al. Down-regulation of stathmin is required for TGF-beta inducible early gene 1 induced growth inhibition of pancreatic cancer cells. Cancer Lett. 2009;274:101-8 pubmed publisher
    ..Small interfering RNAs targeting stathmin inhibited pancreatic cancer cell growth. These suggest that stathmin is a downstream target of TIEG1. ..
  39. Ferraro B, Bepler G, Sharma S, Cantor A, Haura E. EGR1 predicts PTEN and survival in patients with non-small-cell lung cancer. J Clin Oncol. 2005;23:1921-6 pubmed
    ..Identification of patients with low EGR1 therefore may identify patients at high risk for disease recurrence and may also identify patients who have tumors resistant to therapy secondary to loss of pathways such as PTEN. ..
  40. Buitrago M, Lorenz K, Maass A, Oberdorf Maass S, Keller U, Schmitteckert E, et al. The transcriptional repressor Nab1 is a specific regulator of pathological cardiac hypertrophy. Nat Med. 2005;11:837-44 pubmed
    ..These findings implicate the Nab1-Egr1 axis as a crucial regulator of pathological cardiac growth. ..
  41. Guo L, Sans M, Gurda G, Lee S, Ernst S, Williams J. Induction of early response genes in trypsin inhibitor-induced pancreatic growth. Am J Physiol Gastrointest Liver Physiol. 2007;292:G667-77 pubmed
    ..These results indicate that camostat feeding induces a spectrum of early response gene expression and AP-1 DNA binding and that these effects are mainly CCK dependent. ..
  42. Decker E, Nehmann N, Kampen E, Eibel H, Zipfel P, Skerka C. Early growth response proteins (EGR) and nuclear factors of activated T cells (NFAT) form heterodimers and regulate proinflammatory cytokine gene expression. Nucleic Acids Res. 2003;31:911-21 pubmed
    ..Binding of regulatory EGR and NFAT factors to these sites and the functional interaction and formation of stable heterodimeric complexes indicate an important role of these factors for gene transcription. ..
  43. Mitsumoto M, Mitsumoto A, Demple B. Nitric oxide-mediated upregulation of the TGF-beta-inducible early response gene-1 (TIEG1) in human fibroblasts by mRNA stabilization independent of TGF-beta. Free Radic Biol Med. 2003;34:1607-13 pubmed
    ..The TIEG1 mRNA now joins heme oxygenase-1 mRNA in displaying regulation by NO-mediated stabilization. It remains to be determined whether the same control mechanism operates on these and perhaps other messages. ..
  44. Wang Z, Peters B, Klussmann S, Bender H, Herb A, Krieglstein K. Gene structure and evolution of Tieg3, a new member of the Tieg family of proteins. Gene. 2004;325:25-34 pubmed
    ..An interesting explanation for this apparent contradiction might be a homologous recombination leading to loci exchange between the mouse Tieg3 and Tieg2. ..
  45. Russo S, Murrough J, Han M, Charney D, Nestler E. Neurobiology of resilience. Nat Neurosci. 2012;15:1475-84 pubmed publisher
    ..The therapeutic implications of these findings are important and can pave the way for an innovative approach to drug development for a range of stress-related syndromes. ..
  46. Minta J, Yun J, Kabiawu O, Jones J. mRNA differential display identification of vascular smooth muscle early response genes regulated by PDGF. Mol Cell Biochem. 2006;281:63-75 pubmed
    ..Domain analysis of open reading frames suggest that the novel GRSGs may participate in signaling, metabolic, translational or migrational processes during PDGF-induced VSMC activation. ..
  47. Jiang L, Lai Y, Zhang J, Chan C, Lu G, Lin M, et al. Transactivation of the TIEG1 confers growth inhibition of transforming growth factor-?-susceptible hepatocellular carcinoma cells. World J Gastroenterol. 2012;18:2035-42 pubmed publisher
    ..Our data suggest that transactivation of TIEG1 conferred growth inhibition of TGF-?-susceptible human HCC cells. ..
  48. Fueki N, Sagara H, Akimoto K, Ota M, Okada T, Sugiyama K, et al. Interleukin-10 regulates transforming growth factor-beta signaling in cultured human bronchial epithelial cells. Respiration. 2007;74:454-9 pubmed
    ..IL-10 inhibited the expression of TGF-beta-inducible early gene, which is known to downregulate Smad7 expression. Our results suggest that IL-10 acts as a regulatory cytokine in the inhibition of airway inflammation. ..
  49. Chang H, Lin C, Yang C, Liang Y, Yu W. The human papillomavirus-16 (HPV-16) oncoprotein E7 conjugates with and mediates the role of the transforming growth factor-beta inducible early gene 1 (TIEG1) in apoptosis. Int J Biochem Cell Biol. 2010;42:1831-9 pubmed publisher
    ..E7 not only increased the ubiquitination of TIEG1 but also influenced the ability of TIEG1 to affect apoptosis. Our results suggest that suppression of TIEG1-mediated signaling by E7 may contribute to HPV-associated carcinogenesis...
  50. Park H, Kim S, Kim H, Ahn Y, Kang U, Kim Y. Repeated electroconvulsive seizure treatment in rats reduces inducibility of early growth response genes and hyperactivity in response to cocaine administration. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:1014-21 pubmed publisher
    ..In conclusion, repeated ECS treatment reduced the expression and inducibility of Egrs and c-fos, which could attenuate the response of the brain to psychostimulants. ..
  51. Rothe K, Solinski H, Boekhoff I, Gudermann T, Breit A. Morphine activates the E twenty six-like transcription factor-1/serum response factor pathway via extracellular signal-regulated kinases 1/2 in F11 cells derived from dorsal root ganglia neurons. J Pharmacol Exp Ther. 2012;342:41-52 pubmed publisher
    ..Overall, we reveal an important role of ELK-1 for morphine-dependent gene induction in DRG-derived cells and propose that ELK-1 and EGR-4 contribute to the effects of morphine on neuronal plasticity. ..
  52. Alberini C. Transcription factors in long-term memory and synaptic plasticity. Physiol Rev. 2009;89:121-45 pubmed publisher
    ..The results of this work suggest that patterns of transcription regulation represent the molecular signatures of long-term synaptic changes and memory formation. ..
  53. Cook T, Gebelein B, Mesa K, Mladek A, Urrutia R. Molecular cloning and characterization of TIEG2 reveals a new subfamily of transforming growth factor-beta-inducible Sp1-like zinc finger-encoding genes involved in the regulation of cell growth. J Biol Chem. 1998;273:25929-36 pubmed
    ..Thus, TIEG2, together with TIEG1, defines a new subfamily of TGF-beta-inducible Sp1-like proteins involved in the regulation of cell growth. ..