Disease relevance of Sp3

• Sp3-deficient embryos are growth retarded and invariably die at birth of respiratory failure [1].
• We then designed an Sp3-specific ribozyme, expressed it in a human fibrosarcoma cell line in which Sp1 protein and Sp3 protein are expressed at high levels, and found that, indeed, the level of expression of both proteins was significantly reduced [2].
• RESULTS: Tolfenamic acid and structurally related biaryl derivatives induced degradation of Sp1, Sp3, and Sp4 in pancreatic cancer cells [3].
• 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 [4].
• In parallel two known transcriptional regulators of MCAD expression, PPARalpha and Sp3, were concordantly downregulated at 7 days hypoxia [5].

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

• Two forms of the KCS-binding protein complex were demonstrated by electrophoretic mobility shift assay analysis; one contained Sp1 and the other Sp3 [13].
• We therefore investigated the ability of E12.5 Sp3-/- liver cells to contribute to the hematopoietic compartment in an in vivo transplantation assay [32].
• DNA affinity precipitation and chromatin immunoprecipitation assays indicated that binding of Sp1 and Sp3 to this consensus site was increased in B104-1-1 cells [33].
• Western blot analysis of liver nuclear extracts revealed that the levels of Sp3 increase significantly after birth, suggesting a role for the Sp family of transcription factors in controlling the fetal to postnatal increase in GH receptor gene expression [34].
• EMSA and DNA-footprint analysis showed that Sp1 and Sp3 are involved in human prosaposin gene regulation [35].

References