Background: In cancer research, the association between a gene and clinical outcome suggests the underlying etiology of the disease and consequently can motivate further studies. The recent availability of published cancer microarray datasets with clinical annotation provides the opportunity for linking gene expression to prognosis. However, the data are not easy to access and analyze without an effective analysis platform.
Background: Understanding of the firing time determination of replication origins in the entire genome will require a genome‐wide survey of replication origins and their mapping on chromosomes. A microarray technology was applied to obtain a genome‐wide profile of DNA replication and to classify early firing origins. Results: A total of 260 potential replication origins (PROs) were identified in the entire budding yeast genome: 247 as defined peaks on the replication profile and 13 as regions located in the chromosomal termini. Based on the firing time, the 247 PROs were classified into 143 early PROs and 104 late PROs, that were not randomly distributed on chromosomes but formed separated clusters. Most of the early PROs were found to fire in the presence of hydroxyurea, indicating that they were free from the control of the intra‐S‐checkpoint mediated by Mec1 and Rad53. Conclusions: The monitoring method of DNA replication and the analysis method of microarray data used in this study proved powerful for obtaining a genome‐wide view of the initiation and progression of DNA replication.
We have isolated a multicopy suppressor of the temperature-sensitive growth phenotype of organisms carrying mutations of DBF4, a gene that is required for the initiation of chromosomal DNA replication in Saccharomyces cerevisiae and that interacts with the CDC7 protein kinase. periodically during the cell cycle, peaking at the G2/M boundary. CDCS on a multicopy plasmid also suppresses temperature-sensitive cdc15, cdc2O, and dbf2 mutations which affect mitosis during the cell cycle.Protein phosphorylation by protein kinases plays an important role in regulating both the mitotic cell cycle and meiosis in eukaryotes (28, 49). In the yeast Saccharomyces cerevisiae, genes encoding more than 30 protein kinases have been identified (16). Among these, at least four protein kinase genes, CDC28, CDC7, DBF2, and HRR25, are associated with DNA metabolism in the mitotic cell cycle. CDC28 is essential for cell growth and is required both for entry into the S phase and for the G2/M transition (35). Although the cellular abundance of the Cdc28 protein remains constant throughout the cell cycle (30), its protein kinase is periodically active and is regulated by a physical interaction with G, and G2 cyclins (8, 37, 45). CDC7 is also essential for cell growth and is required for the GJIS transition. It has recently been shown that the Cdc7 polypeptide has an associated protein kinase activity and is phosphorylated in vivo (18). Its execution point is just before the initiation of DNA replication (12). After the CDC7 execution point, no protein synthesis is required for the initiation of DNA replication (15). The abundance of the CDC7 transcript remains constant throughout the cell cycle (42), and this is likely to be true for the Cdc7 polypeptide also. However, no direct relationship between the Cdc28 and Cdc7 protein kinases has been elucidated to date.Deletion of DBF2 is not lethal because a homolog ofDBF2 (DBF20) is able to substitute for DBF2 function (48). However, in dbf2 mutants DNA synthesis is transiently delayed and the cell cycle is blocked in late nuclear division at the restrictive temperature, suggesting that the Dbf2 protein is required for completion of the S and M phases (20). The DBF2 transcript accumulates periodically during the cell * Corresponding author.cycle (20), and it is likely that this is also true of the Dbf2 protein. HRR25 is not essential for cell growth, but deletion of HRR25 results in a delay at the G2/M boundary (17), suggesting an important role in the cell cycle. Mutant cells carrying hrr25 exhibit sensitivity to methyl methanesulfonate and X rays (17), suggesting that the gene is also required for DNA repair.In an attempt to identify the various proteins that might interact either with the Cdc7 protein kinase or with both the Cdc28 and Cdc7 protein kinases, we isolated a multicopy suppressor of the temperature-sensitive growth phenotype of organisms carrying cdc7 mutations (24). The suppressor was identified as the DBF4 gene, whose execution point is just before initiation of DNA replication ...
Purpose: EGF receptor (EGFR) and HER2 positivity are considered to be negative prognostic factors in gastric cancer. Biomarker analysis was conducted to evaluate the impact of EGFR and HER2 expression on the outcome of patients enrolled in the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer (ACTS-GC), a randomized controlled trial comparing postoperative adjuvant S-1 therapy with surgery alone in 1,059 patients with stage II/III gastric cancer.Experimental Design: Formalin-fixed, paraffin-embedded surgical specimens were retrospectively examined in 829 patients (78.3%). The effects of EGFR and HER2 positivity on survival were analyzed on the basis of the 5-year survival data from the study. EGFR positivity was defined as an immunohistochemistry (IHC) score of 3þ, and HER2 positivity as an IHC score of 3þ or an IHC score of 2þ with a positive dual-color in situ hybridization status.Results: EGFR and HER2 were positive in 75 (9.0%) and 113 (13.6%) patients, respectively. The overall and relapse-free survival rates were significantly lower in EGFR-positive patients than in EGFR-negative patients, whereas they were similar in HER2-positive and HER2-negative patients. Multivariate analysis showed that EGFR positivity correlated with poor outcomes [HR ¼ 1.504; 95% confidence interval (CI) ¼ 1.020-2.149; P ¼ 0.040]. Treatment with S-1 improved survival compared with surgery alone, irrespective of EGFR and HER2 status.Conclusions: EGFR positivity, but not HER2 positivity, was associated with poor patient outcomes after curative resection of stage II/III gastric cancer. There was no interaction between S-1 and EGFR or HER2 status with respect to survival outcome. Clin Cancer Res; 18(21); 5992-6000. Ó2012 AACR.
Steroid and xenobiotic receptor (SXR) or human pregnane X receptor (hPXR) has been shown to play an important role in
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