Abstract
Sec61\#947; is a subunit of the mammalian endoplasmic reticulum (ER) translocon, an evolutionarily conserved transmembrane protein that moves newly synthesized proteins across the ER. Crystal structures of the bacterial and yeast Sec61 translocon suggest that Sec61 \#945;, \#946; and \#947; subunits form a complex to transport protein from the ribosome into plasma membrane or cytoplasm. Sec61\#947; gene is located on the short arm of chromosome 7, next to the epidermal growth factor receptor (EGFR), and is amplified and over-expressed in every GBM with EGFR amplification. This begs the question whether Sec61\#947; amplification is simply a bystander of EGFR amplification or whether it has independent biological effects. The effect of SEC61\#947; over-expression on GBM behavior is unknown. We used 3 sets of published Affymatrix GBM gene expression data from the University of California, San Francisco (Nigro et al, 2005), M.D Anderson Cancer Center (Phillips et al, 2006) and the University of California, Los Angeles (Freije et al, 2004), and an array of traditional and novel statistical methods, bioinformatics, structural modeling, and biological assays to investigate effects of Sec61\#947; overexpression.Sec61\#947; was associated with poor survival (p=0.005), and was a strong negative predictor for >1 year survival (p=7.6e-6). Furthermore, Sec61\#947; was over-expressed in poorly surviving (mesenchymal and proliferative) GBM, but not in longer surviving (proneural) GBM. The Sec61\#947; gene evolved late in evolution and is conserved among mammals. Structural modeling of the human Sec61 complex indicates similarity to lower species. Human Sec61\#947; is composed of two \#945; helices of unequal length forming a structure that resembles the number "7" with an evolutionarily conserved proline residue at the junction of the arms. TCGA sequencing efforts have not yet detected mutations of this gene. Over-expression of Sec61\#947; in GBM (U251NCI) cells in culture increased growth rate (p<0.05) and survival (p<0.01) but had no obvious effect on cellular morphology, adhesion or migration. Protein-protein interaction database search suggested that Sec61\#947; interacts with 107 known and hypothetical proteins. Pathway enrichment analyses and connectivity mapping indicate associations between Sec61\#947; and 36 biological pathways (e.g., calcium signaling, cell communication etc.). Analysis of gene expression profiles in 195 GBM indicated strong correlation among Sec61\#947; and a few genes of cell cycle pathway; and transcription factors that are members of survival (AKT, NF\#954;\#946;) pathways, suggesting a Sec61\#947; connection to these pathways for exerting its biological effects. We are currently fine mapping and validating sec61\#947; connectivity to major signaling pathways. This work was supported by NIH (NS42927), Diane and Bruce Halle, and the Barrow Neurological Foundation
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2555.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO
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