sp4 transcription factor


Summary: A specificity protein transcription factor that is expressed primarily in the CENTRAL NERVOUS SYSTEM.

Top Publications

  1. 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
  2. ZHOU X, Barrett T, Kelsoe J. Promoter variant in the GRK3 gene associated with bipolar disorder alters gene expression. Biol Psychiatry. 2008;64:104-10 pubmed publisher
    ..The G-384A variant may alter binding of Sp1/Sp4 transcription factors resulting in an increase in gene transcription and an increase in vulnerability to bipolar disorder. ..
  3. Mao X, Yang S, Simpkins J, Barger S. Glutamate receptor activation evokes calpain-mediated degradation of Sp3 and Sp4, the prominent Sp-family transcription factors in neurons. J Neurochem. 2007;100:1300-14 pubmed
    ..These data provide details of an impact of glutamate-receptor activation on molecular events connected to gene expression. ..
  4. Zhou X, Qyang Y, Kelsoe J, Masliah E, Geyer M. Impaired postnatal development of hippocampal dentate gyrus in Sp4 null mutant mice. Genes Brain Behav. 2007;6:269-76 pubmed
    ..The abnormality of the molecular layer was indicated by a reduced level of synaptophysin expression in the mutant mice. The Sp4 transcription factor therefore appears to predominantly regulate the development of dentate granule cells.
  5. Lerner L, Gribanova Y, Ji M, Knox B, Farber D. Nrl and Sp nuclear proteins mediate transcription of rod-specific cGMP-phosphodiesterase beta-subunit gene: involvement of multiple response elements. J Biol Chem. 2001;276:34999-5007 pubmed
    ..We also conclude that Xenopus laevis is an efficient system for analyzing the human beta-PDE promoter and may be used to study other human retinal genes ex vivo and in vivo. ..
  6. Gollner H, Bouwman P, Mangold M, Karis A, Braun H, Rohner I, et al. Complex phenotype of mice homozygous for a null mutation in the Sp4 transcription factor gene. Genes Cells. 2001;6:689-97 pubmed
    ..Thus, the structural similarities, the common recognition motif and the overlapping expression pattern of these three transcription factors do not reflect similar physiological functions. ..
  7. Lerner L, Gribanova Y, Whitaker L, Knox B, Farber D. The rod cGMP-phosphodiesterase beta-subunit promoter is a specific target for Sp4 and is not activated by other Sp proteins or CRX. J Biol Chem. 2002;277:25877-83 pubmed
    ..We found that it binds purified TBP and TFIIB in gel mobility shift assays with cooperative enhancement of binding affinity. ..
  8. Abdelrahim M, Safe S. Cyclooxygenase-2 inhibitors decrease vascular endothelial growth factor expression in colon cancer cells by enhanced degradation of Sp1 and Sp4 proteins. Mol Pharmacol. 2005;68:317-29 pubmed
    ..These results suggest that the antiangiogenic activity of COX-2 inhibitors in colon cancer cells is linked to activation of proteasome-dependent degradation of Sp1 and Sp4 proteins. ..
  9. Zhu H, Nguyen V, Brown A, Pourhosseini A, Garcia A, Van Bilsen M, et al. A novel, tissue-restricted zinc finger protein (HF-1b) binds to the cardiac regulatory element (HF-1b/MEF-2) in the rat myosin light-chain 2 gene. Mol Cell Biol. 1993;13:4432-44 pubmed
    ..These results underscore the complexity of the regulation of the muscle gene program via these AT-rich elements in cardiac and skeletal muscle. ..

More Information


  1. Tsai W, Aiba I, Lee S, Feun L, Savaraj N, Kuo M. Resistance to arginine deiminase treatment in melanoma cells is associated with induced argininosuccinate synthetase expression involving c-Myc/HIF-1alpha/Sp4. Mol Cancer Ther. 2009;8:3223-33 pubmed publisher
    ..Inability of AS induction in A375 cells under arginine depletion conditions was correlated by the failure of c-Myc to interact with the AS promoter. ..
  2. ZHOU X, Tang W, Greenwood T, Guo S, He L, Geyer M, et al. Transcription factor SP4 is a susceptibility gene for bipolar disorder. PLoS ONE. 2009;4:e5196 pubmed publisher
    The Sp4 transcription factor plays a critical role for both development and function of mouse hippocampus. Reduced expression of the mouse Sp4 gene results in a variety of behavioral abnormalities relevant to human psychiatric disorders...
  3. Gao Y, Danciger M, Ozgul R, Gribanova Y, Jacobson S, Farber D. Association of the Asn306Ser variant of the SP4 transcription factor and an intronic variant in the beta-subunit of transducin with digenic disease. Mol Vis. 2007;13:287-92 pubmed
    ..This leaves open the possibility of a cooperative involvement of SP4 and GNB1 in the normal function of the retina. ..
  4. 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. ..
  5. St Amand T, Lu J, Zamora M, Gu Y, Stricker J, Hoshijima M, et al. Distinct roles of HF-1b/Sp4 in ventricular and neural crest cells lineages affect cardiac conduction system development. Dev Biol. 2006;291:208-17 pubmed
    ..Therefore, in this study, we document that a single transcription factor, HF-1b, acts through two separate cell types to direct distinct functions of the cardiac conduction system. ..
  6. Zhou X, Long J, Geyer M, Masliah E, Kelsoe J, Wynshaw Boris A, et al. Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization. Mol Psychiatry. 2005;10:393-406 pubmed
    ..Our studies thus reveal a novel Sp4 pathway that is essential for hippocampal integrity and modulates behavioral processes relevant to psychiatric disorders. ..
  7. Supp D, Witte D, Branford W, Smith E, Potter S. Sp4, a member of the Sp1-family of zinc finger transcription factors, is required for normal murine growth, viability, and male fertility. Dev Biol. 1996;176:284-99 pubmed
    ..sp4/sp4 mutant males fail to copulate, indicating that this gene is required for normal male reproductive behavior. ..
  8. Boutillier S, Lannes B, Buee L, Delacourte A, Rouaux C, Mohr M, et al. Sp3 and sp4 transcription factor levels are increased in brains of patients with Alzheimer's disease. Neurodegener Dis. 2007;4:413-23 pubmed
    ..Our data evidence Sp3 and Sp4 as new hallmarks of AD in postmortem human brains and further point out that Sp proteins are potential triggers of neuronal death signaling cascades. ..
  9. 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
  10. Ramos B, Gaudilliere B, Bonni A, Gill G. Transcription factor Sp4 regulates dendritic patterning during cerebellar maturation. Proc Natl Acad Sci U S A. 2007;104:9882-7 pubmed
    ..These findings indicate that the transcription factor Sp4 controls dendritic patterning during cerebellar development by limiting branch formation and promoting activity-dependent pruning. ..
  11. Lerner L, Peng G, Gribanova Y, Chen S, Farber D. Sp4 is expressed in retinal neurons, activates transcription of photoreceptor-specific genes, and synergizes with Crx. J Biol Chem. 2005;280:20642-50 pubmed
    ..The other Sp family members may be involved in photoreceptor-specific transcription directly or through their competition with Sp4. These data suggest the potential importance of Sp4 in retinal neurobiology and pathology. ..
  12. Nguyêñ Trân V, Kubalak S, Minamisawa S, Fiset C, Wollert K, Brown A, et al. A novel genetic pathway for sudden cardiac death via defects in the transition between ventricular and conduction system cell lineages. Cell. 2000;102:671-82 pubmed
    ..These studies identify a novel genetic pathway for sudden cardiac death via defects in the transition between ventricular and conduction system cell lineages. ..
  13. Hagen G, Muller S, Beato M, Suske G. Cloning by recognition site screening of two novel GT box binding proteins: a family of Sp1 related genes. Nucleic Acids Res. 1992;20:5519-25 pubmed
    ..SPR-2 mRNA is expressed ubiquitously, whereas SPR-1 transcripts are abundant in the brain but barely detectable in other organs. The possible function of these factors for the activity of the uteroglobin promoter is discussed. ..
  14. Pathi S, Jutooru I, Chadalapaka G, Nair V, Lee S, Safe S. Aspirin inhibits colon cancer cell and tumor growth and downregulates specificity protein (Sp) transcription factors. PLoS ONE. 2012;7:e48208 pubmed publisher
  15. Priya A, Johar K, Nair B, Wong Riley M. Specificity protein 4 (Sp4) regulates the transcription of AMPA receptor subunit GluA2 (Gria2). Biochim Biophys Acta. 2014;1843:1196-206 pubmed publisher
    ..Thus, Sp4 and NRF-1 both mediate the tight coupling between neuronal activity and energy metabolism at the transcriptional level. ..
  16. Goldman S, Lovett D, Shalev E. Mechanisms of matrix metalloproteinase-2 (mmp-2) transcriptional repression by progesterone in jar choriocarcinoma cells. Reprod Biol Endocrinol. 2009;7:41 pubmed publisher
    ..This study aimed to explore the mechanism by which progesterone inhibits MMP-2 expression...
  17. Lu S, Archer M. Sp1 coordinately regulates de novo lipogenesis and proliferation in cancer cells. Int J Cancer. 2010;126:416-25 pubmed publisher
    ..Overall, these observations suggest that Sp1 coordinately regulates de novo lipogenesis and proliferation in cancer cells. ..
  18. ZHOU X, Nie Z, Roberts A, Zhang D, Sebat J, Malhotra D, et al. Reduced NMDAR1 expression in the Sp4 hypomorphic mouse may contribute to endophenotypes of human psychiatric disorders. Hum Mol Genet. 2010;19:3797-805 pubmed publisher
    ..Thus, further investigation of the Sp4 pathway may provide novel insights in our understanding of a variety of neuropsychiatric disorders. ..
  19. Batarseh A, Barlow K, Martinez Arguelles D, Papadopoulos V. Functional characterization of the human translocator protein (18kDa) gene promoter in human breast cancer cell lines. Biochim Biophys Acta. 2012;1819:38-56 pubmed publisher
    ..Taken together, these experiments constitute the first in-depth functional analysis of the human TSPO gene promoter and its transcriptional regulation. ..
  20. Priya A, Johar K, Wong Riley M. Specificity protein 4 functionally regulates the transcription of NMDA receptor subunits GluN1, GluN2A, and GluN2B. Biochim Biophys Acta. 2013;1833:2745-2756 pubmed publisher
    ..Our data suggest that Sp4 operates in a complementary and concurrent/parallel manner with NRF-1 and NRF-2 to mediate the tight coupling between energy metabolism and neuronal activity at the molecular level. ..
  21. Ramos B, Valin A, Sun X, Gill G. Sp4-dependent repression of neurotrophin-3 limits dendritic branching. Mol Cell Neurosci. 2009;42:152-9 pubmed publisher
    ..These findings demonstrate that, during cerebellar granule neuron development, Sp4-dependent repression of neurotrophin-3 is required to limit dendritic branching and thereby promote acquisition of the mature dendritic pattern. ..
  22. Pinacho R, Villalmanzo N, Lalonde J, Haro J, Meana J, Gill G, et al. The transcription factor SP4 is reduced in postmortem cerebellum of bipolar disorder subjects: control by depolarization and lithium. Bipolar Disord. 2011;13:474-85 pubmed publisher
  23. Pathi S, Lei P, Sreevalsan S, Chadalapaka G, Jutooru I, Safe S. Pharmacologic doses of ascorbic acid repress specificity protein (Sp) transcription factors and Sp-regulated genes in colon cancer cells. Nutr Cancer. 2011;63:1133-42 pubmed publisher
    ..This study demonstrates for the first time that the anticancer activities of ascorbic acid are due, in part, to ROS-dependent repression of Sp transcription factors. ..
  24. Jutooru I, Guthrie A, Chadalapaka G, Pathi S, Kim K, Burghardt R, et al. Mechanism of action of phenethylisothiocyanate and other reactive oxygen species-inducing anticancer agents. Mol Cell Biol. 2014;34:2382-95 pubmed publisher
  25. Li X, Mertens Talcott S, Zhang S, Kim K, Ball J, Safe S. MicroRNA-27a Indirectly Regulates Estrogen Receptor {alpha} Expression and Hormone Responsiveness in MCF-7 Breast Cancer Cells. Endocrinology. 2010;151:2462-73 pubmed publisher
    ..Thus, miR-27a indirectly regulates E2-responsiveness in MCF-7 cells through suppression of ZBTB10, thereby enhancing expression of ERalpha. ..
  26. Saia G, Lalonde J, Sun X, Ramos B, Gill G. Phosphorylation of the transcription factor Sp4 is reduced by NMDA receptor signaling. J Neurochem. 2014;129:743-52 pubmed publisher
    ..Our findings also suggest that the regulated control of Sp4 activity is an important mechanism governing the developmental patterning of dendrites. ..
  27. Johar K, Priya A, Dhar S, Liu Q, Wong Riley M. Neuron-specific specificity protein 4 bigenomically regulates the transcription of all mitochondria- and nucleus-encoded cytochrome c oxidase subunit genes in neurons. J Neurochem. 2013;127:496-508 pubmed publisher
    ..Sp4 also regulates the three mitochondrial transcription factors (TFAM, TFB1M, and TFB2M) and a COX assembly protein SURF-1 in primary neurons. ..
  28. 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. ..
  29. Hasan N, MacDonald M. Sp/Krüppel-like transcription factors are essential for the expression of mitochondrial glycerol phosphate dehydrogenase promoter B. Gene. 2002;296:221-34 pubmed
    ..The level of Sp1 protein was reduced by 50% in INS-1 cells chronically exposed to a high concentration of glucose. The results demonstrate that Sp/Krüppel-like factors are essential for mGPD gene expression. ..
  30. Fusté M, Pinacho R, Meléndez Pérez I, Villalmanzo N, Villalta Gil V, Haro J, et al. Reduced expression of SP1 and SP4 transcription factors in peripheral blood mononuclear cells in first-episode psychosis. J Psychiatr Res. 2013;47:1608-14 pubmed publisher
    ..Our study shows reduced SP1 and SP4 protein levels in first-episode psychosis in lymphocytes, suggesting that these transcription factors are potential peripheral biomarkers of psychotic spectrum disorders in the early stages. ..
  31. Lee L, Tan Un K, Lin M, Chow B. Retinoic acid activates human secretin gene expression by Sp proteins and nuclear factor I in neuronal SH-SY5Y cells. J Neurochem. 2005;93:339-50 pubmed
    ..We conclude that RA induction of the secretin gene in neuronal cells is regulated by the combined actions of reducing Sp3 and increasing NFI-C expression. ..
  32. Abdelrahim M, Liu S, Safe S. Induction of endoplasmic reticulum-induced stress genes in Panc-1 pancreatic cancer cells is dependent on Sp proteins. J Biol Chem. 2005;280:16508-13 pubmed
    ..This study demonstrates that Sp transcription factors are important for stress-induced responses through their binding to ERSEs. ..
  33. Hammer F, Compagnone N, Vigne J, Bair S, Mellon S. Transcriptional regulation of P450scc gene expression in the embryonic rodent nervous system. Endocrinology. 2004;145:901-12 pubmed
    ..Thus, members of the Sp transcription family play a role in activating P450scc gene transcription in the nervous system, and Ku may further augment this activation. ..
  34. Ma L, Song L, Radoi G, Harrison N. Transcriptional regulation of the mouse gene encoding the alpha-4 subunit of the GABAA receptor. J Biol Chem. 2004;279:40451-61 pubmed
    ..Both Sp3 and Sp4 transcription factors can interact with the two Sp1 binding sites within the minimal promoter and are critical for maximal activity of the promoter in neurons. ..
  35. Villa C, Ghezzi L, Fenoglio C, Clerici F, Marcone A, Benussi L, et al. Genetics and expression analysis of the specificity protein 4 gene (SP4) in patients with Alzheimer's disease and frontotemporal lobar degeneration. J Alzheimers Dis. 2012;31:537-42 pubmed publisher
    ..However, Sp4 mRNA levels are upregulated in patients, possibly resulting in an aberrant expression of downstream target genes involved in the pathogenesis of both diseases. ..
  36. Del Follo Martinez A, Banerjee N, Li X, Safe S, Mertens Talcott S. Resveratrol and quercetin in combination have anticancer activity in colon cancer cells and repress oncogenic microRNA-27a. Nutr Cancer. 2013;65:494-504 pubmed publisher
    ..This was confirmed by transfection of cells with the specific mimic for miR-27a, which partially reversed the effects of RQ. These findings are consistent with previous studies on botanical anticancer agents in colon cancer cells. ..
  37. Chu C, Zavala K, Fahimi A, Lee J, Xue Q, Eilers H, et al. Transcription factors Sp1 and Sp4 regulate TRPV1 gene expression in rat sensory neurons. Mol Pain. 2011;7:44 pubmed publisher
  38. Nair B, Johar K, Priya A, Wong Riley M. Specificity protein 4 (Sp4) transcriptionally regulates inhibitory GABAergic receptors in neurons. Biochim Biophys Acta. 2016;1863:1-9 pubmed publisher
    ..They also indicate that Sp4 is in a position to transcriptionally regulate the balance between excitatory and inhibitory neurochemical expressions in neurons. ..
  39. Shi J, Potash J, Knowles J, Weissman M, Coryell W, Scheftner W, et al. Genome-wide association study of recurrent early-onset major depressive disorder. Mol Psychiatry. 2011;16:193-201 pubmed publisher
    ..Larger samples will be required to confirm the hypothesis of association between MDD (and particularly the recurrent early-onset subtype) and common SNPs. ..
  40. Shyn S, Shi J, Kraft J, Potash J, Knowles J, Weissman M, et al. Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies. Mol Psychiatry. 2011;16:202-15 pubmed publisher
    ..On the basis of previous biological evidence, we consider GRM7 a strong MDD candidate gene. Larger samples will be required to determine whether any common SNPs are significantly associated with MDD. ..
  41. Hewett K, Norman L, Sedmera D, Barker R, Justus C, Zhang J, et al. Knockout of the neural and heart expressed gene HF-1b results in apical deficits of ventricular structure and activation. Cardiovasc Res. 2005;67:548-60 pubmed
  42. Phillips R, Tyson Capper Née Pollard A, Bailey J, Robson S, Europe Finner G. Regulation of expression of the chorionic gonadotropin/luteinizing hormone receptor gene in the human myometrium: involvement of specificity protein-1 (Sp1), Sp3, Sp4, Sp-like proteins, and histone deacetylases. J Clin Endocrinol Metab. 2005;90:3479-90 pubmed
  43. Jin P, Sun Y, Grabowski G. In vivo roles of RORalpha and Sp4 in the regulation of murine prosaposin gene. DNA Cell Biol. 2001;20:781-9 pubmed
    ..These results indicate that Sp4 and RORalpha play minor and major roles, respectively, in regional expression of the prosaposin locus in the brain, whereas expression in the spinal cord is independent of RORalpha. ..
  44. Song J, Mangold M, Suske G, Geltinger C, Kanazawa I, Sun K, et al. Characterization and promoter analysis of the mouse gene for transcription factor Sp4. Gene. 2001;264:19-27 pubmed
    ..We also found that ectopic expression of Sp1 and of MAZ, but not of Sp3, suppressed expression of the Sp4 promoter in a dose-dependent manner. ..
  45. Yamaguchi H, Tanaka K, Kitagawa Y, Miki K. A PEA3 site flanked by SP1, SP4, and GATA sites positively regulates the differentiation-dependent expression of Brachyury in embryonal carcinoma P19 cells. Biochem Biophys Res Commun. 1999;254:542-7 pubmed
    ..Thus, the PEA3 site supported by SP1, SP4, and GATA sites positively regulates the differentiation-dependent expression of Brachyury in P19 cells. ..
  46. Ross R, Navankasattusas S, Harvey R, Chien K. An HF-1a/HF-1b/MEF-2 combinatorial element confers cardiac ventricular specificity and established an anterior-posterior gradient of expression. Development. 1996;122:1799-809 pubmed
    ..The patterned expression of this transgene may provide a model system in which to investigate the cues that dictate anterior-posterior (right ventricle/left ventricle) gradients during mammalian heart development. ..
  47. Kuo M, Savaraj N, Feun L. Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes. Oncotarget. 2010;1:246-51 pubmed
  48. Mao X, Moerman Herzog A, Chen Y, Barger S. Unique aspects of transcriptional regulation in neurons--nuances in NFkappaB and Sp1-related factors. J Neuroinflammation. 2009;6:16 pubmed publisher
    ..These findings and their implications for neuronal differentiation--as well as potential dedifferentiation during degenerative processes--are discussed here. ..
  49. Wu F, Khan S, Wu Q, Barhoumi R, Burghardt R, Safe S. Ligand structure-dependent activation of estrogen receptor alpha/Sp by estrogens and xenoestrogens. J Steroid Biochem Mol Biol. 2008;110:104-15 pubmed publisher
  50. Abdelrahim M, Baker C, Abbruzzese J, Sheikh Hamad D, Liu S, Cho S, et al. Regulation of vascular endothelial growth factor receptor-1 expression by specificity proteins 1, 3, and 4 in pancreatic cancer cells. Cancer Res. 2007;67:3286-94 pubmed
    ..Thus, targeted degradation of Sp proteins is highly effective for inhibiting VEGFR1 and associated angiogenic responses in pancreatic cancer. ..
  51. Hong J, Samudio I, Liu S, Abdelrahim M, Safe S. Peroxisome proliferator-activated receptor gamma-dependent activation of p21 in Panc-28 pancreatic cancer cells involves Sp1 and Sp4 proteins. Endocrinology. 2004;145:5774-85 pubmed
  52. Davis W, Chen Z, Ile K, Tew K. Reciprocal regulation of expression of the human adenosine 5'-triphosphate binding cassette, sub-family A, transporter 2 (ABCA2) promoter by the early growth response-1 (EGR-1) and Sp-family transcription factors. Nucleic Acids Res. 2003;31:1097-107 pubmed
  53. Scohy S, Van Vooren P, Szpirer C, Szpirer J. Assignment1 of Sp genes to rat chromosome bands 7q36 (Sp1), 10q31-->q32.1 (Sp2), 3q24-->q31 (Sp3) and 6q33 (Sp4) and of the SP2 gene to human chromosome bands 17q21.3-->q22 by in situ hybridization. Cytogenet Cell Genet. 1998;81:273-4 pubmed