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Marek's disease virus (MDV), the etiologic agent of Marek's disease, is a potent oncogenic herpesvirus. MDV is highly contagious and elicits a rapid onset of malignant T-cell lymphomas in chickens within several weeks after infection. The MDV genome encodes an oncoprotein, Meq, which shares resemblance with the Jun/Fos family of bZIP transcription factors. Similar to c-Jun, the leucine zipper region of Meq allows the formation of homo- and heterodimers. Meq homo- and heterodimers have different DNA binding affinities and transcriptional activity; therefore, they may differentially regulate transcription of viral and cellular genes. Previous in vitro data has suggested that Meq homodimers may be involved in regulating viral latency/reactivation, while Meq/c-Jun heterodimers are involved in transformation. Therefore, this research investigates the role of Meq homodimers and Meq-Jun heterodimers in the pathogenicity of MDV, by generating chimeric meq genes, which contain the leucine zipper region of the yeast transcription factor GCN4 (meqGCN) or leucine zipper region of c-Fos (meqFos). Thus producing Meq proteins that exclusively homodimerize (MeqGCN) or heterodimerize with Jun family members (MeqFos). Recombinant viruses (rMd5-MeqGCN and rMd5- MeqFos) containing the chimeric genes meqGCN or meqFos, respectively, in place of parental meq were generated with overlapping cosmid clones of Md5, a very virulent MDV strain. The chimeric genes were evaluated in vitro and retained DNA binding and transactivation/repressive functions, however, selected cells expressing MeqGCN and MeqFos had reduced colony formation in soft agar. Both the rMd5-MeqGCN and rMd5- MeqFos viruses replicated in vitro and in vivo, but rMd5-MeqGCN was unable to transform T-cells in infected chickens, while rMd5-MeqFos induced preneoplastic nerve lesions in 50% of infected birds. However, a third virus rMd5-MeqFos/GCN, which contains one copy of each meqGCN and meqFos, induced preneoplastic nerve lesions in 60% of infected chickens and neoplastic lesions in 20% of infected chickens. These data provide the first in vivo evidence that both Meq homodimers and heterodimers are necessary for MDV induced transformation.

The breast cancer susceptibility gene BRCA2 is located on chromosome 13q 12-13. Using breast and ovarian cancers from a BRCA2-linked family, loss of the wild type BRCA2 allele was demonstrated in seven out of eight informative cases (87.5%) indicating that BRCA2 was a recessive oncogene. Analysis of 73 sporadic breast tumours and 12 breast cancer cell lines revealed loss of heterozygosity (LOH) in 22 (30%) of the primary tumours and seven (58%) of the breast cancer cell lines. However, it was not clear from these studies that the target for the observed LOH was the gene BRCA2 or RBl at chromosome 13q14 as the region ofLOH included both genes in all but a single case. Despite the presence of elevated levels of LOH, several separate mutation screening studies of sporadic breast and ovarian tumours have shown that somatic mutations of BRCA2 in sporadic breast and ovarian cancer are very rare. To investigate the possibility that other mechanisms of BRCA2 allelic inactivation might be operative, the methylation status of a CpG island within the promoter region of BRCA2 was examined in 64 sporadic breast tumours and 18 breast and ovarian cancer cell lines. Three CpG dinucleotides within this island were unmethylated in all the normal tissue samples (lymphocytes) examined. These three CpG dinucleotides remained unmethylated in all the breast tumours examined. Moreover, expression of BRCA2 in breast and ovarian cancer cell lines was not obviously correlated with evidence of loss of heterozygosity. These analyses indicate that methylation of the promoter region of BRCA2 and possibly other mechanisms of transcriptional silencing are unlikely to be a common mechanism of gene inactivation in these tumours. To investigate the prevalence of BRCA2 mutations, lymphocyte DNAs from a British, population-based series of 617 breast cancers diagnosed before age 45 were screened for mutations. Mutations were detected in 14 women ( 2.3%, 6/14 43% under age 35 and 8/14 57% age 36-45). This study and a parallel study of BRCA1 demonstrate that BRCA2 and BRCA1 make approximately equal contributions to early onset breast cancer in the UK. Moreover, although BRCA1 and BRCA2 account for breast cancer susceptibility in a substantial proportion of multiple case families, they only account for a small proportion of the overall familial risk conferred by an early onset case. This indicates the existence of other susceptibility genes that are more common but confer lower risks than BRCA1 and BRCA2.

Nck is as an adaptor protein previously implicated in actin cytoskeleton reorganization and by our laboratory, in translation and cell response to stress. Our primary objective was to determine the expression levels of Nck isotypes (Nck-1 and Nck-2) during cancer progression. We have performed western blot analysis of the Nck isotypes expression levels profile in various human cancer cell lines, at different stages of progression. Our data show significantly higher expression levels of Nck-2 protein in metastatic melanomas compared to non-metastatic melanomas and normal melanocytes. Using semi-quantitative RT-PCR, we demonstrated that this increase in Nck-2 expression can be also seen at the transcriptional level. The Ras/RAF/MEK/ERK pathway is often spontaneously activated in melanomas causing hyperactivation of ERK. By downregulating the expression of Nck-2 using siRNA, we have established a strong correlation between increased expression levels of Nck-2 and activated ERK. Furthermore, we have demonstrated the involvement of Nck-2 in cell proliferation and adhesion in metastatic melanomas, revealing that Nck-2 acts as a new player in this disease.

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Urinary bladder urothelial carcinoma is the most common cancer of the urinary tract. About 70% of the diagnosed tumors classified as Non-invasive tumor, which is usually multiple. Despite surgical removal and perioperative chemotherapy, tumor recurrence is not uncommon. However, the chance for such non-invasive tumors to advance to the muscle-invasive stage is relatively small and the 5-year survival rate approaches 95%. The rest 30% are classified as invasive tumors which usually pursue aggressive clinical course. In spite of radical cystectomy in conjunction with debilitating chemotherapy and/or radiotherapy, more than 50% of invasive tumors eventually spread to distant organs. The 5-year survival rate for patients with distant metastasis is only about 6%. The current challenge in the management of urinary bladder carcinoma is the lack of powerful prognostic marker and promising therapeutic agents. Accordingly, to identify novel biomarks to adjust therapeutic strategy is mandatory. The BCL6 proto-oncogene encodes a nuclear transcriptional repressor, it¡¦s inhibits DNA repair pathways and TP53. Perturbation of both these pathways may contribute to normal cell function by repressing DNA damage responses and permitting somatic hypermutation but , in the context of malignancy, this could lead to mutations promoting aggressive tumor. Several studies have demonstrated that BCL6 play a role in different cancer types, however, the function of BCL6 in bladder cancer is understood. Therefore, in this study, we will analyze the endogenous BCL6 mRNA and total/activated BCL6 protein in various bladder cancer cell lines, including BFTC905, and J82. Then we will knockdown of the BCL6 gene by shRNA interference and analyze how it implicates various cellular processes essential to cancerous states. And then we will be analyzed the affection of cell survival, migration and invasion. Conversely, Overexpression of BCL6 in bladder cancer cell lines will be assessed cell proliferation, migration and invasion. Finally, studying it¡¦s affection in vivo. We demonstrate that BCL6 is correlated with bladder cancer.

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