Marek disease virus (MDV) is a herpesvirus of chickens that induces T lymphomas within 3 weeks of infection. The short latency and polyclonal nature of MDVinduced tumors have suggested that the virus may encode one or more direct-acting oncogenes. To date, however, no MDVspecific tumor antigens or candidate transforming genes have been demonstrated. In this paper, we report the identification of a MDV gene encoding a protein with homology to the leucine-zipper class of nuclear oncogenes. It also contains a proline-rich domain characteristic of another class of transcription factors. This gene, designated meq, maps to the long repeat of MDV and is one of the few genes that are highly expressed in MDV-induced T-cell tumors. To our knowledge, a herpesvirus gene closely related to the fos/jun family of oncogenes has not been reported previously.Marek disease virus (MDV) is an avian herpesvirus that causes malignant transformation of T cells in chickens. After a brief cytolytic infection of several days' duration, lymphomas develop at many sites. The short latency and polyclonal nature of the tumors suggest that MDV may encode potent oncogene(s) of its own. Vaccination with a nononcogenic strain or the related avirulent herpesvirus of turkeys can prevent development of lymphoma (1, 2). Although MDV is capable of infecting many chicken cell types, the target cells for transformation have been shown to be limited to a subset of activated T cells (3). Presently, little is known about the putative oncogene(s) of MDV or their cellular targets in lymphocytes.The genome structure of MDV is similar to human alphaherpesviruses (e.g., varicella-zoster virus and herpes simplex virus), with long and short unique regions each bounded by inverted repeats (4). Although characterization of the nucleotide sequence of MDV has only recently begun, mapping data indicate that MDV genes are colinear with varicellazoster virus or herpes simplex virus in the long unique region but differ in organization in both repeats and the short unique region (5, 6). In lytically infected cells, transcription of viral genes throughout the entire MDV genome is detected. By contrast, in MDV-induced lymphoblast tumors, the viral gene expression is limited to areas in or near the repeat regions (7-9).In this paper, we report the identification and characterization of a MDV gene located in the BamHI 12 (Bam 12) fragment of the large repeat, which is highly expressed in MDV-induced T-cell tumors. ¶ This gene encodes a protein of 362 amino acids, which has a leucine zipper repeat and an upstream domain rich in basic amino acids, both characteristics of the fos/jun family of transcriptional activators. It also contains a domain rich in proline residues. We have developed antiserum against a synthetic peptide deduced from the DNA sequence and were able to demonstrate the presence of a 40-kDa protein in a MDV-transformed lymphoblastoid cell line.

Purpose: Activation of mitogen-activated protein kinase (MAPK) and members of the Akt pathway have been shown to promote cell proliferation, survival, and resistance to radiation. This study was conducted to determine whether any of these markers are associated with survival time and response to radiation in glioblastoma. Experimental Design: The expression of phosphorylated (p-)Akt, mammalian target of rapamycin (p-mTOR), p-p70S6K, and p-MAPK were assessed by immunohistochemical staining in 268 cases of newly diagnosed glioblastoma. YKL-40, a prognostic marker previously examined in these tumors, was also included in the analysis. Expression data were tested for correlations with response to radiation therapy in 131 subtotally resected cases and overall survival (in all cases). Results were validated in an analysis of 60 patients enrolled in clinical trials at a second institution. Results: Elevated p-MAPK expression was most strongly associated with poor response to radiotherapy, a finding corroborated in the validation cohort. For survival, higher expressions of p-mTOR, p-p70S6K, and p-MAPK were associated with worse outcome (all P < 0.03). YKL-40 expression was associated with the expressions of p-MAPK, p-mTOR, and p-p70S6K (all P < 0.02), with a trend toward association with p-Akt expression (P = 0.095). When known clinical variables were added to a multivariate analysis, only age, Karnofsky performance score, and p-MAPK expression emerged as independent prognostic factors. Conclusions: p-MAPK and activated members of the Akt pathway are markers of outcome in glioblastoma. Elevated expression of p-MAPK is associated with increased radiation resistance and represents an independent prognostic factor in these tumors.

The tumor suppressor PTEN is mutated or deleted in many tumors, causing the activation of the PI3K pathway. Here, we show that the loss of PTEN increases the transcriptional activity of hypoxiainducible factor 1 (HIF-1) through the inactivation of Forkhead transcription factors (FOXO) in PTEN-null cells.

Purpose The aim of this study was to show preclinical efficacy and clinical development potential of NVP-BKM120, a selective pan class I phosphatidylinositol-3 kinase (PI3K) inhibitor in human glioblastoma (GBM) cells in vitro and in vivo. Experimental Design The effect of NVP-BKM120 on cellular growth was assessed by CellTiter-Blue assay. Flow cytometric analyses were carried out to measure the cell-cycle, apoptosis, and mitotic index. Mitotic catastrophe was detected by immunofluorescence. The efficacy of NVP-BKM120 was tested using intracranial U87 glioma model. Results We tested the biologic effects of a selective PI3K inhibitor NVP-BKM120 in a set of glioma cell lines. NVP-BKM120 treatment for 72 hours resulted in a dose-dependent growth inhibition and effectively blocked the PI3K/Akt signaling cascade. Although we found no obvious relationship between the cell line's sensitivity to NVP-BKM120 and the phosphatase and tensin homolog (PTEN) and epidermal growth factor receptor (EGFR) statuses, we did observe a differential sensitivity pattern with respect to p53 status, with glioma cells containing wild-type p53 more sensitive than cells with mutated or deleted p53. NVP-BKM120 showed differential forms of cell death on the basis of p53 status of the cells with p53 wild-type cells undergoing apoptotic cell death and p53 mutant/deleted cells having a mitotic catastrophe cell death. NVP-BKM120 mediates mitotic catastrophe mainly through Aurora B kinase. Knockdown of p53 in p53 wild-type U87 glioma cells displayed microtubule misalignment, multiple centrosomes, and mitotic catastrophe cell death. Parallel to the assessment of the compound in in vitro settings, in vivo efficacy studies using an intracranial U87 tumor model showed an increased median survival from 26 days (control cohort) to 38 and 48 days (treated cohorts). Conclusion Our present findings establish that NVP-BKM120 inhibits the PI3K signaling pathways, leading to different forms of cell death on the basis of p53 statuses. Further studies are warranted to determine if NVP-BKM120 has potential as a glioma treatment.