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Gene Review

Sp3  -  trans-acting transcription factor 3

Mus musculus

Synonyms: D130027J01Rik, Transcription factor Sp3
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Disease relevance of Sp3


High impact information on Sp3

  • This modification of Sp3 causes decreased binding of the repressor complex to a glucose-responsive GC box in the angiopoietin-2 promoter, resulting in increased Ang-2 expression [6].
  • It is also selective, operating only on the promoter, but not enhancers, of oct4; both a putative Sp1/Sp3 and a GGGAGGG binding site are required for demethylation and transcription [7].
  • Down-regulation of GHR expression was associated with reduced nuclear abundance and DNA binding of the GHR gene-promoter transactivator, Sp3 [8].
  • Comparison of the Sp1 and Sp3 knockout phenotype shows that Sp1 and Sp3 have distinct functions in vivo, but also suggests a degree of functional redundancy [1].
  • In Sp3 null mice, the dentin/enamel layer of the developing teeth is impaired due to the lack of ameloblast-specific gene products [1].

Biological context of Sp3

  • Conversely, binding of Sp3 to these elements decreased while Sp1 binding increased with nuclear extracts from plantaris muscle exposed to mechanical overload, a stimulus that increases betaMyHC gene expression [9].
  • This study demonstrates that increased binding of Sp3 to GC-rich elements in the betaMyHC promoter is a critical event in down-regulation of betaMyHC gene expression under non-weight-bearing conditions [9].
  • We speculate that phosphorylated CREB and Sp3 also interacted to bring about GLUT 3 expression in response to development/cell differentiation and neurotransmission [10].
  • BACKGROUND: Sp4 is a zinc finger transcription factor which is closely related to Sp1 and Sp3 [11].
  • CONCLUSIONS: The phenotype of the Sp4null mice differs significantly from those described for Sp1-/- and Sp3-/- mice [11].

Anatomical context of Sp3

  • In corroboration, efficient promoter activity was restored in differentiated muscle cells by exogenous expression of Sp1 and Sp3 [12].
  • In mouse cells null for all Sp3 isoforms, PKR expression was reduced to approximately 50% that of wild-type cells in the absence of IFN [13].
  • Endogenous Sp1 and Sp3 proteins were detected only in myoblasts and not in myotubes, which indicates that the lack of these factors causes down-regulation of the Dp71 promoter activity in differentiated cells [12].
  • Binding of Sp1/Sp3 to a proximal GC-box at -64/-46 bp was enhanced by FSH in immature granulosa cells but reduced after human chorionic gonadotropin stimulation of preovulatory follicles despite constant protein expression [14].
  • Differential utilization of the promoter of peripheral-type benzodiazepine receptor by steroidogenic versus nonsteroidogenic cell lines and the role of Sp1 and Sp3 in the regulation of basal activity [15].

Associations of Sp3 with chemical compounds

  • Coimmunoprecipitation and glutathione S-transferase pull-down experiments demonstrate that c-Myc may form complexes with Sp1/Sp3 [16].
  • We previously showed, using P19 cells as a model system, that the lamin A/C promoter has a retinoic acid-responsive element (L-RARE), and that Sp1 and Sp3 bind the CACCC box of the L-RARE [17].
  • Substitution of the amino acid triplet KEE by alanine residues within this region changed the almost transcriptionally inactive Sp3 into a strong activator [18].
  • In addition, we have identified Sp3, another member of the Sp1 family of transcription factors, as a second factor that can bind to the glucose response elements of PII [19].
  • Furthermore, the expression level of Sp3 was decreased when Neuro2A cells were demethylated with 5-aza-2'-deoxycytidine, and increasing Sp3 levels in Schneider's Drosophila line 2 cells led to the repression of mDOR promoter activity when the promoter was methylated [20].

Physical interactions of Sp3

  • Specific ablation of the Sp1/Sp3 binding site significantly decreased Rac2 promoter activity in both RAW 264.7 and NIH-3T3 cells [21].
  • GHR expression was reduced in BDL mice; in liver, this was associated with reduced Sp3 binding to a GHR gene promoter cis element [22].
  • We find several E-box and Sp1/Sp3 binding sites as well as three putative p53 binding sites that are conserved in the human promoter sequence [23].
  • The related Sp3 protein also bound this same region of mouse Glut 3 in all three cell lines [24].

Regulatory relationships of Sp3

  • Sp1 and Sp3 activate CTalpha gene transcription through sequence specific binding within three promoter domains [25].
  • These results show that the Sp3 protein is involved in regulating Fas gene expression in lung epithelial cells [26].
  • Both Sp1 and Sp3 are responsible for p21waf1 promoter activity induced by histone deacetylase inhibitor in NIH3T3 cells [27].
  • On the other hand, using the TATA-containing reporter plasmid BCAT-2, Sp3 coexpression significantly repressed Sp1-induced trans-activation, although Sp3 alone was ineffective [28].
  • These results demonstrate an important functionality of Sp1 and Sp3 in regulating the expression of the mouse nestin gene [29].

Other interactions of Sp3

  • Antibody "supershift" studies demonstrated that members of the Sp (Sp1, Sp3) and nuclear hormone receptor [chicken ovalbumin upstream promoter transcription factor (COUP-TF)/erbA-related protein 3] families interact with the pressure overload-responsive unit [30].
  • Unlike Sp1 and Sp3, which are ubiquitous proteins, Sp4 is highly abundant in the central nervous system, but also detectable in many other tissues [11].
  • Their essential role in bone ossification apparently involves Sp3, and in lung maturation Sp3 together with TTF-1 [31].
  • The lungs displayed reduced air space in the IGF-I-deficient embryos and neonates, phenotype exacerbated in the double nulls, which showed abnormal epithelial cells and decreased Sp3 expression [31].
  • Our data suggest that Sp1, Sp3, and c-Jun play an important role in gene expression through the L-RARE during RA treatment [17].

Analytical, diagnostic and therapeutic context of Sp3


  1. Transcription factor Sp3 is essential for post-natal survival and late tooth development. Bouwman, P., Göllner, H., Elsässer, H.P., Eckhoff, G., Karis, A., Grosveld, F., Philipsen, S., Suske, G. EMBO J. (2000) [Pubmed]
  2. Identification of the promoter of human transcription factor Sp3 and evidence of the role of factors Sp1 and Sp3 in the expression of Sp3 protein. Lou, Z., Maher, V.M., McCormick, J.J. Gene (2005) [Pubmed]
  3. Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation. Abdelrahim, M., Baker, C.H., Abbruzzese, J.L., Safe, S. J. Natl. Cancer Inst. (2006) [Pubmed]
  4. Basal transcription activity of the dyskeratosis congenita gene is mediated by Sp1 and Sp3 and a patient mutation in a Sp1 binding site is associated with decreased promoter activity. Salowsky, R., Heiss, N.S., Benner, A., Wittig, R., Poustka, A. Gene (2002) [Pubmed]
  5. Counter-regulatory effects of incremental hypoxia on the transcription of a cardiac fatty acid oxidation enzyme-encoding gene. Ngumbela, K.C., Sack, M.N., Essop, M.F. Mol. Cell. Biochem. (2003) [Pubmed]
  6. Methylglyoxal modification of mSin3A links glycolysis to angiopoietin-2 transcription. Yao, D., Taguchi, T., Matsumura, T., Pestell, R., Edelstein, D., Giardino, I., Suske, G., Ahmed, N., Thornalley, P.J., Sarthy, V.P., Hammes, H.P., Brownlee, M. Cell (2006) [Pubmed]
  7. DNA demethylation is necessary for the epigenetic reprogramming of somatic cell nuclei. Simonsson, S., Gurdon, J. Nat. Cell Biol. (2004) [Pubmed]
  8. Tumor necrosis factor alpha blockade restores growth hormone signaling in murine colitis. DiFedele, L.M., He, J., Bonkowski, E.L., Han, X., Held, M.A., Bohan, A., Menon, R.K., Denson, L.A. Gastroenterology (2005) [Pubmed]
  9. Sp3 proteins negatively regulate beta myosin heavy chain gene expression during skeletal muscle inactivity. Tsika, G., Ji, J., Tsika, R. Mol. Cell. Biol. (2004) [Pubmed]
  10. Trans-activators regulating neuronal glucose transporter isoform-3 gene expression in mammalian neurons. Rajakumar, A., Thamotharan, S., Raychaudhuri, N., Menon, R.K., Devaskar, S.U. J. Biol. Chem. (2004) [Pubmed]
  11. Complex phenotype of mice homozygous for a null mutation in the Sp4 transcription factor gene. Göllner, H., Bouwman, P., Mangold, M., Karis, A., Braun, H., Rohner, I., Del Rey, A., Besedovsky, H.O., Meinhardt, A., van den Broek, M., Cutforth, T., Grosveld, F., Philipsen, S., Suske, G. Genes Cells (2001) [Pubmed]
  12. Dystrophin Dp71 expression is down-regulated during myogenesis: role of Sp1 and Sp3 on the Dp71 promoter activity. de León, M.B., Montañez, C., Gómez, P., Morales-Lázaro, S.L., Tapia-Ramírez, V., Valadez-Graham, V., Recillas-Targa, F., Yaffe, D., Nudel, U., Cisneros, B. J. Biol. Chem. (2005) [Pubmed]
  13. Activation of the RNA-dependent protein kinase PKR promoter in the absence of interferon is dependent upon Sp proteins. Das, S., Ward, S.V., Tacke, R.S., Suske, G., Samuel, C.E. J. Biol. Chem. (2006) [Pubmed]
  14. Egr-1 induction in rat granulosa cells by follicle-stimulating hormone and luteinizing hormone: combinatorial regulation by transcription factors cyclic adenosine 3',5'-monophosphate regulatory element binding protein, serum response factor, sp1, and early growth response factor-1. Russell, D.L., Doyle, K.M., Gonzales-Robayna, I., Pipaon, C., Richards, J.S. Mol. Endocrinol. (2003) [Pubmed]
  15. Differential utilization of the promoter of peripheral-type benzodiazepine receptor by steroidogenic versus nonsteroidogenic cell lines and the role of Sp1 and Sp3 in the regulation of basal activity. Giatzakis, C., Papadopoulos, V. Endocrinology (2004) [Pubmed]
  16. Myc represses the p21(WAF1/CIP1) promoter and interacts with Sp1/Sp3. Gartel, A.L., Ye, X., Goufman, E., Shianov, P., Hay, N., Najmabadi, F., Tyner, A.L. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  17. c-Jun and Sp1 family are critical for retinoic acid induction of the lamin A/C retinoic acid-responsive element. Okumura, K., Hosoe, Y., Nakajima, N. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  18. An inhibitor domain in Sp3 regulates its glutamine-rich activation domains. Dennig, J., Beato, M., Suske, G. EMBO J. (1996) [Pubmed]
  19. Sp1 mediates glucose activation of the acetyl-CoA carboxylase promoter. Daniel, S., Kim, K.H. J. Biol. Chem. (1996) [Pubmed]
  20. Transcriptional regulation of mouse delta-opioid receptor gene by CpG methylation: involvement of Sp3 and a methyl-CpG-binding protein, MBD2, in transcriptional repression of mouse delta-opioid receptor gene in Neuro2A cells. Wang, G., Wei, L.N., Loh, H.H. J. Biol. Chem. (2003) [Pubmed]
  21. Identification and functional characterization of the murine Rac2 gene promoter. Ou, X., Pollock, J., Dinauer, M.C., Gharehbaghi-Schnell, E., Skalnik, D.G. DNA Cell Biol. (1999) [Pubmed]
  22. Alterations in growth hormone receptor abundance regulate growth hormone signaling in murine obstructive cholestasis. Held, M.A., Cosme-Blanco, W., Difedele, L.M., Bonkowski, E.L., Menon, R.K., Denson, L.A. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  23. The activity of the murine Bax promoter is regulated by Sp1/3 and E-box binding proteins but not by p53. Schmidt, T., Körner, K., Karsunky, H., Korsmeyer, S., Müller, R., Möröy, T. Cell Death Differ. (1999) [Pubmed]
  24. Sp1 and Sp3 regulate transcriptional activity of the facilitative glucose transporter isoform-3 gene in mammalian neuroblasts and trophoblasts. Rajakumar, R.A., Thamotharan, S., Menon, R.K., Devaskar, S.U. J. Biol. Chem. (1998) [Pubmed]
  25. Functional significance of Sp1, Sp2, and Sp3 transcription factors in regulation of the murine CTP:phosphocholine cytidylyltransferase alpha promoter. Bakovic, M., Waite, K.A., Vance, D.E. J. Lipid Res. (2000) [Pubmed]
  26. Sp3 regulates fas expression in lung epithelial cells. Pang, H., Miranda, K., Fine, A. Biochem. J. (1998) [Pubmed]
  27. Both Sp1 and Sp3 are responsible for p21waf1 promoter activity induced by histone deacetylase inhibitor in NIH3T3 cells. Xiao, H., Hasegawa, T., Isobe, K. J. Cell. Biochem. (1999) [Pubmed]
  28. Sp family transcription factors regulate expression of rat D2 dopamine receptor gene. Yajima, S., Lee, S.H., Minowa, T., Mouradian, M.M. DNA Cell Biol. (1998) [Pubmed]
  29. Characterization and promoter analysis of the mouse nestin gene. Cheng, L., Jin, Z., Liu, L., Yan, Y., Li, T., Zhu, X., Jing, N. FEBS Lett. (2004) [Pubmed]
  30. A role for Sp and nuclear receptor transcription factors in a cardiac hypertrophic growth program. Sack, M.N., Disch, D.L., Rockman, H.A., Kelly, D.P. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  31. Developmental cooperation of leukemia inhibitory factor and insulin-like growth factor I in mice is tissue-specific and essential for lung maturation involving the transcription factors Sp3 and TTF-1. Pichel, J.G., Fernández-Moreno, C., Vicario-Abejón, C., Testillano, P.S., Patterson, P.H., de Pablo, F. Mech. Dev. (2003) [Pubmed]
  32. Impaired hematopoiesis in mice lacking the transcription factor Sp3. Van Loo, P.F., Bouwman, P., Ling, K.W., Middendorp, S., Suske, G., Grosveld, F., Dzierzak, E., Philipsen, S., Hendriks, R.W. Blood (2003) [Pubmed]
  33. HER-2/neu represses the metastasis suppressor RECK via ERK and Sp transcription factors to promote cell invasion. Hsu, M.C., Chang, H.C., Hung, W.C. J. Biol. Chem. (2006) [Pubmed]
  34. Role of the Sp family of transcription factors in the ontogeny of growth hormone receptor gene expression. Yu, J.H., Schwartzbauer, G., Kazlman, A., Menon, R.K. J. Biol. Chem. (1999) [Pubmed]
  35. Isolation and characterization of the human prosaposin promoter. Sun, Y., Jin, P., Witte, D.P., Grabowski, G.A. Gene (1998) [Pubmed]
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