Disease relevance of GSPT1

• Thus, our results show that the GGC expansion may have a potential role in regulating eRF3/GSPT1 expression and/or changing the protein function that can lead to gastric cancer development [1].
• RESULTS: Different histological types of gastric tumours were analysed and nine of the 25 tumours revealed eRF3/GSPT1 overexpression; moreover, eight of the 12 intestinal type carcinomas analysed overexpressed the gene, whereas eRF3/GSPT1 was overexpressed in only one of the 10 diffuse type carcinomas (Kruskal-Wallis Test; p < 0.05) [2].
• A breakpoint for nonrandom chromosome rearrangements has been found in the region of GSPT1 in patients with acute nonlymphocytic leukemia [3].
• This p53 polymorphism modulates risk to smoking-induced lung cancer independently of other genetic risk factors such as germ line polymorphism of CYP1A1 or GST1 genes [4].
• Earlier studies have revealed that human cytomegalovirus rapidly inhibits the growth of fibroblasts, blocking cell cycle progression at multiple points, including the G1-to-S-phase transition [5].

High impact information on GSPT1

• CUL-2 is required for the G1-to-S-phase transition and mitotic chromosome condensation in Caenorhabditis elegans [6].
• A human homologue (GST1-Hs) of the yeast GST1 gene that encodes a new GTP-binding protein essential for the G1-to-S phase transition of the cell cycle was cloned from the cDNA library of human KB cells [7].
• When expressed in yeast cell, the GST1-Hs gene could complement the ts phenotype of yeast gst1 mutant [7].
• The regions potentially responsible for GTP binding and GTP hydrolysis were conserved in the GST1-Hs protein as well [7].
• The GST1-Hs cDNA contained a 1497 bp open reading frame coding for a 499 amino acid protein with mol. wt 55,754 and with the amino acid sequence homologies of 52.3 and 37.8% to the GST1 protein and polypeptide chain elongation factor EF1 alpha respectively [7].

Chemical compound and disease context of GSPT1

• Polyglycine expansions in eRF3/GSPT1 are associated with gastric cancer susceptibility [1].

Biological context of GSPT1

• The mouse GSPT1 was expressed in a proliferation-dependent manner in Swiss 3T3 cells, whereas the expression of GSPT2 was constant during the cell-cycle progression [8].
• Here we propose that GSPT2 originated through retrotransposition of processed GSPT1 transcript into the genome [9].
• Additionally, processed GSPT1 interacts biochemically with IAPs and could promote caspase activation, IAP ubiquitination and apoptosis [10].
• The aim of this study was to evaluate eRF3/GSPT1 gene as a potential genetic susceptibility associated locus for gastric cancer, analysing a stable GGC expansion in exon 1 encoding a polyglycine tract in the N-terminal domain of the protein [1].
• No correlation was found between ploidy and transcript expression levels of eRF3/GSPT1 [2].

Anatomical context of GSPT1

• Immunoprecipitation assays in COS-7 cells expressing flag epitope-tagged proteins demonstrated that not only GSPT1 but also GSPT2 was capable of interacting with eRF1 [8].
• E2F-1, a member of the E2F transcription factor family, contributes to the regulation of the G1-to-S phase transition in higher eukaryotic cells [11].
• Although the inhibition of the GSPT-PABP interaction did not affect the de novo formation of an 80 S ribosomal initiation complex, it appears to suppress the subsequent recycle of ribosome [12].
• Furthermore, NF-kappaB promotes G1-to-S-phase transition in mouse embryonal fibroblasts and in T47D mammary carcinoma cells [13].
• A-myb is expressed in bovine vascular smooth muscle cells during the late G1-to-S phase transition and cooperates with c-myc to mediate progression to S phase [14].

Associations of GSPT1 with chemical compounds

• The Bcr-Abl tyrosine kinase activates mitogenic signaling pathways and stimulates G1-to-S phase transition in hematopoietic cells [15].
• HMBA alters factors controlling G1-to-S phase transition, leading to G1 arrest and inhibition of DNA synthesis [16].

Physical interactions of GSPT1

• We identify and characterize the human translation termination factor eRF3/GSPT1 as an interacting partner of RNase L [17].
• Search for other GSPT-binding proteins in yeast two-hybrid screening system resulted in the identification of a cDNA encoding polyadenylate-binding protein (PABP), whose amino terminus is associating with the poly(A) tail of mRNAs presumably for their stabilization [18].

Regulatory relationships of GSPT1

• By measuring the readthrough at a premature nonsense codon in a reporter mRNA, we found that eRF3a silencing induced an important increase in readthrough whereas eRF3b silencing had no significant effect [19].
• Finally, our data indicate that the expression level of eRF3a controls the formation of the termination complex by modulating eRF1 protein stability [19].
• Unregulated expression of the transcription factor E2F promotes the G1-to-S phase transition in cultured mammalian cells [20].

Other interactions of GSPT1

• Overexpression of eRF3/GSPT1 was not associated with increased translation rates because the upregulation of eRF3/GSPT1 did not correlate with increased eRF1 levels [2].
• A novel role of the mammalian GSPT/eRF3 associating with poly(A)-binding protein in Cap/Poly(A)-dependent translation [12].
• This domain recruits a series of translation factors including poly(A)-interacting proteins (Paip1 and Paip2) and release factor 3 (RF3/GSPT) to the initiation complex on mRNA [21].
• Instead, we find that the activation of cyclin E-associated kinase that normally accompanies the G1-to-S phase transition is inhibited [22].
• Cyclins E and A in association with Cdk2 have been shown to play a role in the G1-to-S phase transition in mammalian cells [22].

Analytical, diagnostic and therapeutic context of GSPT1

• Southern blot hybridization with a panel of human-rodent somatic cells confirmed the location of the GSPT1 gene on chromosome 16 and also showed the existence of a homologous gene on the X chromosome [3].
• The GSPT1 gene, a human homolog of the yeast GST1 gene (formerly named GST1-Hs), was mapped on human chromosome 16p13.1 by a combination of nonradioactive in situ hybridization and Giemsa staining [3].

References