Thus, alternative splicing of the NFX1 transcript plays an important role in the expression of gene in human fetal kidney cells. 2.3.7. may be possible to inhibit malignancy growth by interfering with telomerase activity. Expression and function of gene are known to be regulated at numerous molecular levels. However, the transcription of has been suggested to be the dominant step in the regulation of telomerase activity [7,26]. Previous studies on promoter have MKC9989 defined a core region encompassing 330 bp upstream of the translation start site to 228 bp downstream, extending right into the second exon of the gene [28,29,30]. A number of transcription factor binding sites have been recognized in this core promoter. However, the molecular mechanism underlying gene activation during induced Pluripotent Stem (iPS) cell reprogramming [31,32] and gene silencing during cellular differentiation remains largely unclear. On the other hand, recent studies have revealed the potential role of promoter mutations and chromosomal rearrangements in the activation of telomerase in malignancy cells. These results have provided potential new strategies in targeting telomerase for malignancy therapy. Here, we summarize the recent improvements in the understanding of the transcriptional regulation of gene, focusing our attention on trans-acting factors, namely transcription factors and epigenetic MKC9989 modifiers, as well as genetic alterations in proximal region. 2. Trans-Acting Regulators of Transcription The core promoter of the gene contains several known regulatory elements including GC-motifs and E-boxes. Several other articles have elegantly examined the roles specific factors or protein families Rabbit Polyclonal to MYLIP play in the modulation of gene expression. Here, we have chosen to focus only on factors which have been reported to bind directly to the promoter region via in vitro or in vivo DNACprotein conversation assays, such as chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) (refer to Table 1 for the complete list of factors). We selected a number of well-studied factors in each category and briefly discuss its role in the regulation of the gene, specifically highlighting the complexity of the regulatory network involved in controlling the expression of proximal promoter with regards to the numerous response elements enclosed in this region (refer to Physique 1 for any schematic of the binding sites of selected transcription factors found in this region). Open in a separate window Physique 1 Schematic of transcription factor binding sites in human Telomerase Reverse Transcriptase (translation start site (+1) is usually represented by the gray box. Horizontal lines above and below the box show approximate binding sites of respective transcription factors. Blue lines: hotspot promoter mutations (-124 corresponds to C228T mutation; -146 corresponds to C250T mutation); green: activator; reddish: repressor; purple: regulator with dual functions; dotted collection: regulator bound to sites produced by hotspot mutations. Table 1 List of factors reported to bind to human Telomerase Reverse Transcriptase (gene is usually one of them; c-Myc binds to two E-box sequences found on the core promoter of gene [45,46]. In addition, overexpression of c-Myc in squamous cell carcinoma cells and human foreskin keratinocyte cells resulted in the upregulation of the promoter activity . The MKC9989 transcription activating role of c-Myc on gene MKC9989 is usually mediated by the recruitment of the histone acetyltransferase (HAT) complex called SPT3-TAF9-GCN5 acetyltransferase complex (STAGA) and the transcription co-activator Mediator complex . On the other hand, c-Myc alone may not be sufficient to drive the activation of expression. E6-transduced human foreskin keratinocytes (HFKs) did not show an increase in c-Myc expression, even though the cells achieved replicative immortality . This suggests that additional factors may be required in order to upregulate expression in these cells. Indeed, c-Myc was found to act cooperatively with Specificity Protein 1 (Sp1) in the activation of transcription via combinatorial binding of these two factors on their respective cis elements in the promoter . When the E-boxes and GC-rich motifs (response elements of Sp1) were mutated, E6-mediated activation of telomerase expression was abolished. This also explains the observation that c-Myc and Sp1 expression correlates with transcription in various malignancy cell lines. Besides Sp1, numerous other factors play a role in modulating c-Myc-mediated regulation.