Prognostic model of pulmonary adenocarcinoma by expression profiling of eight genes as determined by quantitative real-time reverse transcriptase polymerase chain reaction
JOURNAL OF CLINICAL ONCOLOGY
Authors: Endoh, H; Tomida, S; Yatabe, Y; Konishi, H; Osada, H; Tajima, K; Kuwano, T; Takahashi, T; Mitsudomi, T
Abstract
Purpose Recently, several expression-profiling experiments have shown that adenocarcinoma can be classified into subgroups that also reflect patient survival. In this study, we examined the expression patterns of 44 genes selected by these studies to test whether their expression patterns were relevant to prognosis in our cohort as well, and to create a prognostic model applicable to clinical practice, Patients and Methods Expression levels were determined in 85 adenocarcinoma patients by quantitative reverse transcriptase polymerase chain reaction. Cluster analysis was performed, and a prognostic model was created by the proportional hazards model using a stepwise method. Results Hierarchical clustering divided the cases into three major groups, and group B, comprising 21 cases, had significantly poor survival (P = .0297). Next, we tried to identify a smaller number of genes of particular predictive value, and eight genes (PTK7, CIT, SCNN1A, PGES, ERO1L, ZWINT, and two ESTs) were selected. We then calculated a risk index that was defined as a linear combination of gene expression values weighted by their estimated regression coefficients. The risk index was a significant independent prognostic factor (P = .0021) by multivariate analysis. Furthermore, the robustness of this model was confirmed using an independent set of 21 patients (P = .0085). Conclusion By analyzing a reasonably small number of genes, patients with adenocarcinoma could be stratified according to their prognosis. The prognostic model could be applicable to future decisions concerning treatment. (C) 2004 by American Society of Clinical Oncology.
Ero1L, a thiol oxidase, is required for Notch signaling through cysteine bridge formation of the Lin12-Notch repeats in Drosophila melanogaster
JOURNAL OF CELL BIOLOGY
Authors: Tien, An-Chi; Rajan, Akhila; Schulze, Karen L.; Ryoo, Hyung Don; Acar, Melih; Steller, Hermann; Bellen, Hugo J.
Abstract
Notch-mediated cell-cell communication regulates numerous developmental processes and cell fate decisions. Through a mosaic genetic screen in Drosophila melanogaster, we identified a role in Notch signaling for a conserved thiol oxidase, endoplasmic reticulum (ER) oxidoreductin 1-like (Ero1L). Although Ero1L is reported to play a widespread role in protein folding in yeast, in flies Ero1L mutant clones show specific defects in lateral inhibition and inductive signaling, two characteristic processes regulated by Notch signaling. Ero1L mutant cells accumulate high levels of Notch protein in the ER and induce the unfolded protein response, suggesting that Notch is misfolded and fails to be exported from the ER. Biochemical assays demonstrate that Ero1L is required for formation of disulfide bonds of three Lin12-Notch repeats (LNRs) present in the extracellular domain of Notch. These LNRs are unique to the Notch family of proteins. Therefore, we have uncovered an unexpected requirement for Ero1L in the maturation of the Notch receptor.