sp3 transcription factor


Summary: A specificity protein transcription factor that contains three C-terminal CYS2-HIS2 ZINC FINGERS. It regulates expression of a variety of genes including VASCULAR ENDOTHELIAL GROWTH FACTOR and CYCLIN-DEPENDENT KINASE INHIBITOR P27.

Top Publications

  1. Kramps C, Strieder V, Sapetschnig A, Suske G, Lutz W. E2F and Sp1/Sp3 Synergize but are not sufficient to activate the MYCN gene in neuroblastomas. J Biol Chem. 2004;279:5110-7 pubmed
  2. Gingras M, Larouche K, Larouche N, Leclerc S, Salesse C, Guérin S. Regulation of the integrin subunit alpha5 gene promoter by the transcription factors Sp1/Sp3 is influenced by the cell density in rabbit corneal epithelial cells. Invest Ophthalmol Vis Sci. 2003;44:3742-55 pubmed
  3. Van Loo P, Mahtab E, Wisse L, Hou J, Grosveld F, Suske G, et al. Transcription factor Sp3 knockout mice display serious cardiac malformations. Mol Cell Biol. 2007;27:8571-82 pubmed
    ..Wt1 expression was diminished in epicardium-derived cells in the myocardium of Sp3 null hearts. We conclude that Sp3 is required for normal cardiac development and suggest that it has a crucial role in myocardial differentiation. ..
  4. Li L, Davie J. The role of Sp1 and Sp3 in normal and cancer cell biology. Ann Anat. 2010;192:275-83 pubmed publisher
    ..In this review, the role of Sp1 and Sp3 in normal and cancer cell biology and the multiple mechanisms deciding the functional roles of Sp1 and Sp3 will be presented. ..
  5. Lou Z, O Reilly S, Liang H, Maher V, Sleight S, McCormick J. Down-regulation of overexpressed sp1 protein in human fibrosarcoma cell lines inhibits tumor formation. Cancer Res. 2005;65:1007-17 pubmed
    ..These data indicate that overexpression of Sp1 plays a causal role in malignant transformation of human fibroblasts and suggest that for cancers in which it is overexpressed, Sp1 constitutes a target for therapy. ..
  6. Chadalapaka G, Jutooru I, Burghardt R, Safe S. Drugs that target specificity proteins downregulate epidermal growth factor receptor in bladder cancer cells. Mol Cancer Res. 2010;8:739-50 pubmed publisher
    ..Thus, compounds such as curcumin and BA that downregulate Sp transcription factors represent a novel class of anticancer drugs that target EGFR in bladder cancer cells and tumors by inhibiting receptor expression. ..
  7. Stains J, Lecanda F, Screen J, Towler D, Civitelli R. Gap junctional communication modulates gene transcription by altering the recruitment of Sp1 and Sp3 to connexin-response elements in osteoblast promoters. J Biol Chem. 2003;278:24377-87 pubmed
    ..Thus, regulation of Sp1/Sp3 recruitment to the promoter may represent a potential general mechanism for transcriptional control of target genes by signals passing through gap junctions. ..
  8. Chou S, Chen H, Lu S. Sp1 and Sp3 are involved in up-regulation of human deoxyribonuclease II transcription during differentiation of HL-60 cells. Eur J Biochem. 2003;270:1855-62 pubmed
    ..We therefore conclude that Sp1 and/or Sp3 are involved in the up-regulation of DNase II expression during the differentiation of HL-60 cells. ..
  9. Van Loo P, Bouwman P, Ling K, Middendorp S, Suske G, Grosveld F, et al. Impaired hematopoiesis in mice lacking the transcription factor Sp3. Blood. 2003;102:858-66 pubmed
    ..Thus, the absence of Sp3 results in cell-autonomous hematopoietic defects, affecting in particular the erythroid and myeloid cell lineages. ..

More Information


  1. Sapetschnig A, Koch F, Rischitor G, Mennenga T, Suske G. Complexity of translationally controlled transcription factor Sp3 isoform expression. J Biol Chem. 2004;279:42095-105 pubmed
    ..The transcriptional activity of all the Sp3 isoforms is regulated by SUMO modification. Our results demonstrate that Sp3 has many unique features and is not simply a functional equivalent of Sp1. ..
  2. Garcia Dominguez M, Reyes J. SUMO association with repressor complexes, emerging routes for transcriptional control. Biochim Biophys Acta. 2009;1789:451-9 pubmed publisher
  3. Dunzendorfer S, Lee H, Tobias P. Flow-dependent regulation of endothelial Toll-like receptor 2 expression through inhibition of SP1 activity. Circ Res. 2004;95:684-91 pubmed
    ..These results extend the role of flow in controlling endothelial responsiveness. Given the current evidence that TLRs are proatherogenic, flow suppression of TLR2 expression may be atheroprotective. ..
  4. Krüger I, Vollmer M, Simmons D, Simmons D, Elsässer H, Philipsen S, et al. Sp1/Sp3 compound heterozygous mice are not viable: impaired erythropoiesis and severe placental defects. Dev Dyn. 2007;236:2235-44 pubmed
    ..Our findings demonstrate that a threshold of Sp1 and Sp3 activity is required for normal embryonic development, suggesting that Sp1 and Sp3 act cooperatively to regulate downstream targets. ..
  5. Higgins K, Abdelrahim M, Liu S, Yoon K, Safe S. Regulation of vascular endothelial growth factor receptor-2 expression in pancreatic cancer cells by Sp proteins. Biochem Biophys Res Commun. 2006;345:292-301 pubmed
    ..These results suggest that VEGFR2 cannot only be targeted by receptor tyrosine kinase inhibitors but also by drugs that downregulate Sp proteins or block Sp-dependent transactivation. ..
  6. Qin K, Rosenfield R. Characterization of the basal promoter element of the human type 5 17beta-hydroxysteroid dehydrogenase gene. Biochim Biophys Acta. 2005;1728:115-25 pubmed
    ..These results indicate that members of the Sp family of transcription factors play an important role in regulating constitutive and stimulated expression of the HSD17B5 gene in H295R cells. ..
  7. Pages G. Sp3-mediated VEGF regulation is dependent on phosphorylation by extra-cellular signals regulated kinases (Erk). J Cell Physiol. 2007;213:454-63 pubmed
    ..Altogether our results described a new link between constitutive Erk activity and the regulation of VEGF expression two common denominators implicated in tumor angiogenesis. ..
  8. Aoyama T, Okamoto T, Kohno Y, Fukiage K, Otsuka S, Furu M, et al. Cell-specific epigenetic regulation of ChM-I gene expression: crosstalk between DNA methylation and histone acetylation. Biochem Biophys Res Commun. 2008;365:124-30 pubmed
    ..These results represent an example of the plasticity of differentiation being regulated by the cell-specific plasticity of epigenetic regulation. ..
  9. Stielow B, Sapetschnig A, Wink C, Krüger I, Suske G. SUMO-modified Sp3 represses transcription by provoking local heterochromatic gene silencing. EMBO Rep. 2008;9:899-906 pubmed publisher
    ..These results indicate that SUMOylation has a crucial role in regulating gene expression by initiating chromatin structure changes that render DNA inaccessible to the transcription machinery. ..
  10. Zaniolo K, Rufiange A, Leclerc S, Desnoyers S, Guérin S. Regulation of the poly(ADP-ribose) polymerase-1 gene expression by the transcription factors Sp1 and Sp3 is under the influence of cell density in primary cultured cells. Biochem J. 2005;389:423-33 pubmed
    ..PARP-1 gene expression therefore appears to be co-ordinated with that of Sp1 and Sp3 in primary cultured cells, suggesting that PARP-1 may play some important functions during the proliferative burst that characterizes wound healing. ..
  11. Spengler M, Kennett S, Moorefield K, Simmons S, Brattain M, Horowitz J. Sumoylation of internally initiated Sp3 isoforms regulates transcriptional repression via a Trichostatin A-insensitive mechanism. Cell Signal. 2005;17:153-66 pubmed
    ..We conclude that Sp3 isoforms are sumoylated in vivo and this post-translational modification plays an important role in the regulation of Sp3-mediated transcription. ..
  12. Amin M, Malakooti J, Sandoval R, Dudeja P, Ramaswamy K. IFN-gamma and TNF-alpha regulate human NHE3 gene expression by modulating the Sp family transcription factors in human intestinal epithelial cell line C2BBe1. Am J Physiol Cell Physiol. 2006;291:C887-96 pubmed
    ..Our data indicate that IFN-gamma and TNF-alpha may repress the NHE3 promoter activity in C2BBe1 cells by PKA-mediated phosphorylation of Sp1 and Sp3 transcription factors. ..
  13. Liu A, Hoffman P, Lu W, Bai G. NF-kappaB site interacts with Sp factors and up-regulates the NR1 promoter during neuronal differentiation. J Biol Chem. 2004;279:17449-58 pubmed
    ..We conclude that the NF-kappaB site positively regulates the NR1 promoter during neuronal differentiation via interacting mainly with Sp factors and neuronal differentiation reduces the effect of Sp3 factor on this site. ..
  14. Yu B, Datta P, Bagchi S. Stability of the Sp3-DNA complex is promoter-specific: Sp3 efficiently competes with Sp1 for binding to promoters containing multiple Sp-sites. Nucleic Acids Res. 2003;31:5368-76 pubmed
    ..Taken together, this study provides a possible mechanism of the promoter-specific transcription repression function of Sp3. ..
  15. Chadjichristos C, Ghayor C, Kypriotou M, Martin G, Renard E, Ala Kokko L, et al. Sp1 and Sp3 transcription factors mediate interleukin-1 beta down-regulation of human type II collagen gene expression in articular chondrocytes. J Biol Chem. 2003;278:39762-72 pubmed
    ..Altogether, these data indicate that modulation of Sp3/Sp1 ratio in cartilage could be a potential target to prevent or limit the tissue degradation. ..
  16. Cao Y, Ramirez M, Williams M. Enhanced binding of Sp1/Sp3 transcription factors mediates the hyperoxia-induced increased expression of the lung type I cell gene T1alpha. J Cell Biochem. 2003;89:887-901 pubmed
    ..However, the abundance of nuclear Sp1 increases after short hyperoxic exposures, suggesting that signaling pathways activated by hyperoxia lead to Sp protein translocation, perhaps as a result of increased Sp phosphorylation. ..
  17. Williams A, Isaacs R, Stowell K. Down-regulation of human topoisomerase IIalpha expression correlates with relative amounts of specificity factors Sp1 and Sp3 bound at proximal and distal promoter regions. BMC Mol Biol. 2007;8:36 pubmed
    ..Competition between Sp1 and Sp3 for the same cognate DNA would result in activation or repression depending on absolute amounts of each transcription factor in cells treated with doxorubicin. ..
  18. Zhang X, Li Y, Dai C, Yang J, Mundel P, Liu Y. Sp1 and Sp3 transcription factors synergistically regulate HGF receptor gene expression in kidney. Am J Physiol Renal Physiol. 2003;284:F82-94 pubmed
    ..Our findings suggest that HGF may have a broader spectrum of target cells and possess wider implications in kidney structure and function than originally thought. ..
  19. Koutsodontis G, Moustakas A, Kardassis D. The role of Sp1 family members, the proximal GC-rich motifs, and the upstream enhancer region in the regulation of the human cell cycle inhibitor p21WAF-1/Cip1 gene promoter. Biochemistry. 2002;41:12771-84 pubmed
  20. Li D, Mitchell D, Luo J, Yi Z, Cho S, Guo J, et al. Estrogen regulates KiSS1 gene expression through estrogen receptor alpha and SP protein complexes. Endocrinology. 2007;148:4821-8 pubmed
  21. Jang S, Steinert P. Loricrin expression in cultured human keratinocytes is controlled by a complex interplay between transcription factors of the Sp1, CREB, AP1, and AP2 families. J Biol Chem. 2002;277:42268-79 pubmed
    ..Together, these events allow loricrin transcription to proceed. Indeed, the synergistic effects of the Sp1, c-Jun, and p300 factors indicate that p300/CBP might act as bridge to form an active transcription complex. ..
  22. Abdelrahim M, Baker C, Abbruzzese J, Safe S. Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation. J Natl Cancer Inst. 2006;98:855-68 pubmed
    ..009) than tumors from control mice. Tolfenamic acid is a new antipancreatic cancer NSAID that activates degradation of transcription factors Sp1, Sp3, and Sp4; reduces VEGF expression; and decreases tumor growth and metastasis. ..
  23. Ellis D, Dehm S, Bonham K. The modification of Sp3 isoforms by SUMOylation has differential effects on the SRC1A promoter. Gene. 2006;379:68-78 pubmed
    ..These results provide new insights into the complexity of Sp3 mediated transcription which appears to be highly dependent on the isoform bound, SUMOylation status and the promoter context. ..
  24. Zaniolo K, Gingras M, Audette M, Guérin S. Expression of the gene encoding poly(ADP-ribose) polymerase-1 is modulated by fibronectin during corneal wound healing. Invest Ophthalmol Vis Sci. 2006;47:4199-210 pubmed
  25. Chirakkal H, Leech S, Brookes K, Prais A, Waby J, Corfe B. Upregulation of BAK by butyrate in the colon is associated with increased Sp3 binding. Oncogene. 2006;25:7192-200 pubmed
    ..We have shown that both Sp1 and Sp3 bind, but upon butyrate treatment Sp1 binding decreases in favour of Sp3 binding. We speculate that this may be an acetylation-mediated event. ..
  26. Li L, He S, Sun J, Davie J. Gene regulation by Sp1 and Sp3. Biochem Cell Biol. 2004;82:460-71 pubmed
    ..Regulation of the transcriptional activity of Sp1 and Sp3 occurs largely at the post-translational level. In this review, we focus on the roles of Sp1 and Sp3 in the regulation of gene expression. ..
  27. Irvine S, Foka P, Rogers S, Mead J, Ramji D. A critical role for the Sp1-binding sites in the transforming growth factor-beta-mediated inhibition of lipoprotein lipase gene expression in macrophages. Nucleic Acids Res. 2005;33:1423-34 pubmed
    ..These results, therefore, suggest a novel mechanism for the TGF-beta-mediated repression of LPL gene transcription that involves regulation of the action of Sp1 and Sp3. ..
  28. Moran K, Crusio R, Chan C, Grekova M, Richert J. Human transcription factor Sp3: genomic structure, identification of a processed pseudogene, and transcript analysis. Gene. 2004;341:235-47 pubmed
    ..Each sequenced transcript possesses three to five potential translation initiation sites. This diversity at the level of gene expression will likely be key to understanding the diverse functions of Sp3. ..
  29. Abdelrahim M, Smith R, Burghardt R, Safe S. Role of Sp proteins in regulation of vascular endothelial growth factor expression and proliferation of pancreatic cancer cells. Cancer Res. 2004;64:6740-9 pubmed
  30. Hasleton M, Ibbitt J, Hurst H. Characterization of the human activator protein-2gamma (AP-2gamma) gene: control of expression by Sp1/Sp3 in breast tumour cells. Biochem J. 2003;373:925-32 pubmed
    ..We propose that differences in the level and activity of Sp3 between breast tumour lines can determine the expression level of their AP-2gamma gene. ..
  31. Ryu H, Lee J, Zaman K, Kubilis J, Ferrante R, Ross B, et al. Sp1 and Sp3 are oxidative stress-inducible, antideath transcription factors in cortical neurons. J Neurosci. 2003;23:3597-606 pubmed
    ..Taken together, these results establish Sp1 and Sp3 as oxidative stress-induced transcription factors in cortical neurons that positively regulate neuronal survival. ..
  32. Beauchef G, Bigot N, Kypriotou M, Renard E, Porée B, Widom R, et al. The p65 subunit of NF-?B inhibits COL1A1 gene transcription in human dermal and scleroderma fibroblasts through its recruitment on promoter by protein interaction with transcriptional activators (c-Krox, Sp1, and Sp3). J Biol Chem. 2012;287:3462-78 pubmed publisher
    ..In conclusion, our findings highlight a new mechanism for COL1A1 transcriptional regulation by NF-?B, and these data could allow the development of new antifibrotic strategies. ..
  33. Wierstra I. Sp1: emerging roles--beyond constitutive activation of TATA-less housekeeping genes. Biochem Biophys Res Commun. 2008;372:1-13 pubmed publisher
  34. Kolell K, Crawford D. Evolution of Sp transcription factors. Mol Biol Evol. 2002;19:216-22 pubmed
    ..These results suggest that these different domains have different evolutionary histories. ..
  35. Jutooru I, Chadalapaka G, Lei P, Safe S. Inhibition of NFkappaB and pancreatic cancer cell and tumor growth by curcumin is dependent on specificity protein down-regulation. J Biol Chem. 2010;285:25332-44 pubmed publisher
  36. Sapetschnig A, Rischitor G, Braun H, Doll A, Schergaut M, Melchior F, et al. Transcription factor Sp3 is silenced through SUMO modification by PIAS1. EMBO J. 2002;21:5206-15 pubmed
    ..SUMO-modified Sp3 bound to DNA with similar specificity and affinity as unmodified Sp3. However, DNA-bound Sp3 did not act as a substrate for SUMO modification. ..
  37. Zhang J, Wang S, Wesley R, Danner R. Adjacent sequence controls the response polarity of nitric oxide-sensitive Sp factor binding sites. J Biol Chem. 2003;278:29192-200 pubmed
    ..These results define a composite element that can utilize secondary inputs to convert off signals to on, thereby conferring complex functionalities to the same DNA binding motif. ..
  38. Ganapathy M, Ghosh R, Jianping X, Zhang X, Bedolla R, Schoolfield J, et al. Involvement of FLIP in 2-methoxyestradiol-induced tumor regression in transgenic adenocarcinoma of mouse prostate model. Clin Cancer Res. 2009;15:1601-11 pubmed publisher
    ..Targeting Sp1-mediated FLIP signaling pathway may provide a novel approach for prostate cancer management. ..
  39. Miki N, Ikuta M, Matsui T. Hypoxia-induced activation of the retinoic acid receptor-related orphan receptor alpha4 gene by an interaction between hypoxia-inducible factor-1 and Sp1. J Biol Chem. 2004;279:15025-31 pubmed
  40. Sade H, Holloway K, Romero I, Male D. Transcriptional control of occludin expression in vascular endothelia: regulation by Sp3 and YY1. Biochim Biophys Acta. 2009;1789:175-84 pubmed
  41. Da L, Li D, Yokoyama K, Li T, Zhao M. Dual promoters control the cell-specific expression of the human cell death-inducing DFF45-like effector B gene. Biochem J. 2006;393:779-88 pubmed
    ..Thus our analysis revealed a novel mechanism for the cell-specific transcription of the human CIDE-B gene, which involves epigenetic and genetic control at separate respective promoters. ..
  42. Katsuyama M, Hirai H, Iwata K, Ibi M, Matsuno K, Matsumoto M, et al. Sp3 transcription factor is crucial for transcriptional activation of the human NOX4 gene. FEBS J. 2011;278:964-72 pubmed publisher
    ..Taken together, these results suggest that Sp3 plays a key role in the expression of NOX4 in various cell lineages in humans. ..
  43. Choi H, Hwang C, Kim C, Song K, Law P, Wei L, et al. Transcriptional regulation of mouse mu opioid receptor gene: Sp3 isoforms (M1, M2) function as repressors in neuronal cells to regulate the mu opioid receptor gene. Mol Pharmacol. 2005;67:1674-83 pubmed
    ..These results suggest that the binding of the M1 and M2 isoforms of the Sp3 transcription factor to the Sp binding sequence may play a role in mouse MOR gene expression.
  44. Essafi Benkhadir K, Grosso S, Puissant A, Robert G, Essafi M, Deckert M, et al. Dual role of Sp3 transcription factor as an inducer of apoptosis and a marker of tumour aggressiveness. PLoS ONE. 2009;4:e4478 pubmed publisher
    ..Full length Sp3 accumulation highlights bypass of tumour cell apoptotic capacities and is indicative of head and neck tumours aggressiveness. ..
  45. Ma W, Horvath G, Kistler M, Kistler W. Expression patterns of SP1 and SP3 during mouse spermatogenesis: SP1 down-regulation correlates with two successive promoter changes and translationally compromised transcripts. Biol Reprod. 2008;79:289-300 pubmed publisher
    ..As part of this work, we also identified five additional, minor Sp1 cap sites by 5' rapid amplification of cDNA ends, including a trans-spliced RNA originating from the Glcci1 gene. ..
  46. Ross S, Best J, Zon L, Gill G. SUMO-1 modification represses Sp3 transcriptional activation and modulates its subnuclear localization. Mol Cell. 2002;10:831-42 pubmed
    ..These studies reveal a direct effect of SUMO-1 modification on activity of a dual function transcription factor and provide a mechanism for functional specificity within the Sp transcription factor family. ..
  47. Chadjichristos C, Ghayor C, Herrouin J, Ala Kokko L, Suske G, Pujol J, et al. Down-regulation of human type II collagen gene expression by transforming growth factor-beta 1 (TGF-beta 1) in articular chondrocytes involves SP3/SP1 ratio. J Biol Chem. 2002;277:43903-17 pubmed
    ..These findings suggest that TGF-beta1 inhibition of COL2A1 gene transcription in RAC is mediated by an increase of the Sp3/Sp1 ratio and by the repression of Sp1 transactivating effects on that gene. ..
  48. Sun J, Chen H, Moniwa M, Litchfield D, Seto E, Davie J. The transcriptional repressor Sp3 is associated with CK2-phosphorylated histone deacetylase 2. J Biol Chem. 2002;277:35783-6 pubmed
    ..CK2 phosphorylation of HDAC2 recruited by Sp1 or Sp3 could regulate HDAC activity and alter the balance of histone deacetylase and histone acetyltransferase activities and dynamic chromatin remodeling of estrogen-regulated genes. ..
  49. Zhang Y, Dufau M. Silencing of transcription of the human luteinizing hormone receptor gene by histone deacetylase-mSin3A complex. J Biol Chem. 2002;277:33431-8 pubmed
  50. Cheng Y, Imir A, Suzuki T, Fenkci V, Yilmaz B, Sasano H, et al. SP1 and SP3 mediate progesterone-dependent induction of the 17beta hydroxysteroid dehydrogenase type 2 gene in human endometrium. Biol Reprod. 2006;75:605-14 pubmed
  51. Chang Y, Wang L, Suh Y, Mao L, Karpen S, Khuri F, et al. Mechanisms underlying lack of insulin-like growth factor-binding protein-3 expression in non-small-cell lung cancer. Oncogene. 2004;23:6569-80 pubmed
    ..Thus interference with Sp-1 transactivation by MeCP2 may contribute to the transcriptional defect of IGFBP-3 expression in NSCLC cells with methylated promoter. ..
  52. Rohr O, Aunis D, Schaeffer E. COUP-TF and Sp1 interact and cooperate in the transcriptional activation of the human immunodeficiency virus type 1 long terminal repeat in human microglial cells. J Biol Chem. 1997;272:31149-55 pubmed
    ..These findings reveal how the novel interplay of Sp1 and COUP-TF families of transcription factors regulate HIV-1 gene expression. ..
  53. Gollner H, Dani C, Phillips B, Philipsen S, Suske G. Impaired ossification in mice lacking the transcription factor Sp3. Mech Dev. 2001;106:77-83 pubmed
    ..The capacity of Sp3-/- cells to undergo osteogenic differentiation in vitro is reduced and osteocalcin expression is significantly diminished. Our studies establish Sp3 as an essential transcription factor for late bone development. ..