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Gene Review

Sp4  -  trans-acting transcription factor 4

Mus musculus

Synonyms: 5730497N03Rik, HF-1b, HF1-b, Transcription factor Sp4
 
 
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Disease relevance of Sp4

  • RESULTS: Tolfenamic acid and structurally related biaryl derivatives induced degradation of Sp1, Sp3, and Sp4 in pancreatic cancer cells [1].
  • Mice deficient for HF-1 b survive to term and exhibit normal cardiac structure and function but display sudden cardiac death and a complete penetrance of conduction system defects, including spontaneous ventricular tachycardia and a high incidence of AV block [2].
  • OBJECTIVE: Knockout of the neural and cardiac expressed transcription factor HF-1b causes electrophysiological abnormalities including fatal ventricular arrhythmias that occur with increasing frequency around the 4th week of postnatal life [3].
 

High impact information on Sp4

  • HF-1 b, an SP1 -related transcription factor, is preferentially expressed in the cardiac conduction system and ventricular myocytes in the heart [2].
  • Sp3 is a ubiquitously expressed human transcription factor closely related to Sp1 and Sp4 [4].
  • By immunofluorescence and western analysis, the transcription factor Hf1b/Sp4 and the gap junction proteins connexin 40 and connexin 43 were misexpressed and/or mislocalized in LmnaN195K/N195K hearts [5].
  • The region proximal to the transcription initiation site at -127 bound Sp1, Sp3, and Sp4, and the distal region at -143 bound E2F-4-DP-1-p107 [6].
  • An HF-1a/HF-1b/MEF-2 combinatorial element confers cardiac ventricular specificity and established an anterior-posterior gradient of expression [7].
 

Biological context of Sp4

  • 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 [8].
  • RESULTS: We have disrupted the mouse Sp4 gene by a targeted deletion of the exons encoding the N-terminal activation domains [9].
  • We report here the isolation and characterization of the gene for Sp4 from a mouse genomic library [10].
  • Complex phenotype of mice homozygous for a null mutation in the Sp4 transcription factor gene [9].
  • The mouse gene for Sp4 was about 80 kb in length and it consisted of six exons and five introns [10].
 

Anatomical context of Sp4

  • Unlike Sp1 and Sp3, which are ubiquitous proteins, Sp4 is highly abundant in the central nervous system, but also detectable in many other tissues [9].
  • 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 [11].
  • Absence of HF-1b in the neural crest led to atrial and atrioventricular dysfunction resulting from deficiencies in the neurotrophin receptor trkC [12].
 

Other interactions of Sp4

 

Analytical, diagnostic and therapeutic context of Sp4

  • These analyses indicated that relative to controls, the apical ventricular territory of the HF-1b knockout had reductions in the density of small resistance vessels (p<0.01) and deficits in arterial function as assayed by bead perfusion (p<0.01) [3].

References

  1. 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]
  2. A novel genetic pathway for sudden cardiac death via defects in the transition between ventricular and conduction system cell lineages. Nguyên-Trân, V.T., Kubalak, S.W., Minamisawa, S., Fiset, C., Wollert, K.C., Brown, A.B., Ruiz-Lozano, P., Barrere-Lemaire, S., Kondo, R., Norman, L.W., Gourdie, R.G., Rahme, M.M., Feld, G.K., Clark, R.B., Giles, W.R., Chien, K.R. Cell (2000) [Pubmed]
  3. Knockout of the neural and heart expressed gene HF-1b results in apical deficits of ventricular structure and activation. Hewett, K.W., Norman, L.W., Sedmera, D., Barker, R.J., Justus, C., Zhang, J., Kubalak, S.W., Gourdie, R.G. Cardiovasc. Res. (2005) [Pubmed]
  4. An inhibitor domain in Sp3 regulates its glutamine-rich activation domains. Dennig, J., Beato, M., Suske, G. EMBO J. (1996) [Pubmed]
  5. Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice. Mounkes, L.C., Kozlov, S.V., Rottman, J.N., Stewart, C.L. Hum. Mol. Genet. (2005) [Pubmed]
  6. Inhibition of cyclin D1 kinase activity is associated with E2F-mediated inhibition of cyclin D1 promoter activity through E2F and Sp1. Watanabe, G., Albanese, C., Lee, R.J., Reutens, A., Vairo, G., Henglein, B., Pestell, R.G. Mol. Cell. Biol. (1998) [Pubmed]
  7. An HF-1a/HF-1b/MEF-2 combinatorial element confers cardiac ventricular specificity and established an anterior-posterior gradient of expression. Ross, R.S., Navankasattusas, S., Harvey, R.P., Chien, K.R. Development (1996) [Pubmed]
  8. Transcriptional regulation of the mouse gene encoding the alpha-4 subunit of the GABAA receptor. Ma, L., Song, L., Radoi, G.E., Harrison, N.L. J. Biol. Chem. (2004) [Pubmed]
  9. 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]
  10. Characterization and promoter analysis of the mouse gene for transcription factor Sp4. Song, J., Mangold, M., Suske, G., Geltinger, C., Kanazawa, I., Sun, K., Yokoyama, K.K. Gene (2001) [Pubmed]
  11. In vivo roles of RORalpha and Sp4 in the regulation of murine prosaposin gene. Jin, P., Sun, Y., Grabowski, G.A. DNA Cell Biol. (2001) [Pubmed]
  12. Distinct roles of HF-1b/Sp4 in ventricular and neural crest cells lineages affect cardiac conduction system development. St Amand, T.R., Lu, J.T., Zamora, M., Gu, Y., Stricker, J., Hoshijima, M., Epstein, J.A., Ross, J.J., Ruiz-Lozano, P., Chien, K.R. Dev. Biol. (2006) [Pubmed]
  13. Positive regulatory elements (HF-1a and HF-1b) and a novel negative regulatory element (HF-3) mediate ventricular muscle-specific expression of myosin light-chain 2-luciferase fusion genes in transgenic mice. Lee, K.J., Hickey, R., Zhu, H., Chien, K.R. Mol. Cell. Biol. (1994) [Pubmed]
  14. Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization. Zhou, X., Long, J.M., Geyer, M.A., Masliah, E., Kelsoe, J.R., Wynshaw-Boris, A., Chien, K.R. Mol. Psychiatry (2005) [Pubmed]
 
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