Abstract:A total of 40 human brain tumor samples were analyzed for tumor-specific alterations at the RB1 gene locus. Gliomas were more prevalent in younger males and meningiomas in older females. Southern blot analysis revealed loss of heterozygosity (LOH) at the intron 1 locus of RB1 gene in 19.4% of informative cases and this is the first report showing LOH at this locus in human brain tumors. Levels of RB1 mRNA and protein, pRb, and the percentage of hyperphosphorylated form of pRb were also analyzed in these tumors… Show more
“…) and minimal signal using phospho‐RB1‐specific antibodies (Figs 7 and ). In contrast, elevated expression of hyperphosphorylated RB1, or loss/inactivation of RB1, has been described in most human glioma samples . Recent studies have suggested a more complex role for RB1 family proteins with RB1 acting as a molecular adaptor at the crossroads of multiple pathways, depending on cellular context .…”
In this study, we determined the expression of key signalling pathway proteins TP53, MDM2, P21, AKT, PTEN, RB1, P16, MTOR and MAPK in canine gliomas using western blotting. Protein expression was defined in three canine astrocytic glioma cell lines treated with CCNU, temozolamide or CPT-11 and was further evaluated in 22 spontaneous gliomas including high and low grade astrocytomas, high grade oligodendrogliomas and mixed oligoastrocytomas. Response to chemotherapeutic agents and cell survival were similar to that reported in human glioma cell lines. Alterations in expression of key human gliomagenesis pathway proteins were common in canine glioma tumour samples and segregated between oligodendroglial and astrocytic tumour types for some pathways. Both similarities and differences in protein expression were defined for canine gliomas compared to those reported in human tumour counterparts. The findings may inform more defined assessment of specific signalling pathways for targeted therapy of canine gliomas.
“…) and minimal signal using phospho‐RB1‐specific antibodies (Figs 7 and ). In contrast, elevated expression of hyperphosphorylated RB1, or loss/inactivation of RB1, has been described in most human glioma samples . Recent studies have suggested a more complex role for RB1 family proteins with RB1 acting as a molecular adaptor at the crossroads of multiple pathways, depending on cellular context .…”
In this study, we determined the expression of key signalling pathway proteins TP53, MDM2, P21, AKT, PTEN, RB1, P16, MTOR and MAPK in canine gliomas using western blotting. Protein expression was defined in three canine astrocytic glioma cell lines treated with CCNU, temozolamide or CPT-11 and was further evaluated in 22 spontaneous gliomas including high and low grade astrocytomas, high grade oligodendrogliomas and mixed oligoastrocytomas. Response to chemotherapeutic agents and cell survival were similar to that reported in human glioma cell lines. Alterations in expression of key human gliomagenesis pathway proteins were common in canine glioma tumour samples and segregated between oligodendroglial and astrocytic tumour types for some pathways. Both similarities and differences in protein expression were defined for canine gliomas compared to those reported in human tumour counterparts. The findings may inform more defined assessment of specific signalling pathways for targeted therapy of canine gliomas.
“…U87dEGFR cells have a wild-type p53 gene with EGFRvIII expression and inactivation of p16 and PTEN. Consistent with this deregulation, these cells have an increase in the level of total pRb protein and mostly in the hyperphosphorylated form (31,32), which leads to release of E2F-1 and stimulates cells to bypass the G 0 -G 1 checkpoint and enter into S phase. However, this unscheduled entry into S phase can trigger apoptosis when deregulated E2F-1 activity reaches a certain threshold induced by an DNA-damaging agent (33).…”
Targeted therapies directed against individual cancer-specific molecular alterations offer the development of diseasespecific and individualized treatment strategies. Activation of the transcription factor E2F-1 via alteration of the p16-cyclinD-Rb pathway is one of the key molecular events in the development of gliomas. E2F-1 binds to and activates the E2F-1 promoter in an autoregulatory manner. The human E2F-1 promoter has been shown to be selectively activated in tumor cells with a defect in the pRb pathway. Paradoxically, E2F-1 also carries tumor suppressor function. Our investigations focused on analyzing the dynamics of the activity of the E2F-1 responsive element under basal conditions and certain stimuli such as chemotherapy using molecular imaging technology. We constructed a retrovirus bearing the Cis-E2F-TA-LITG reporter system to noninvasively assess E2F-1-dependent transcriptional regulation in culture and in vivo. We show that our reporter system is sensitive to monitor various changes in cellular E2F-1 levels and its transcriptional control of our reporter system to follow the state of the Rb/E2F pathway and the DNA damage-induced up-regulation of E2F-1 activity in vivo. Exposure to 1,3-bis(2-chloroethyl)-1-nitrosourea leads to increased E2F-1 expression levels in a dose-and time-dependent manner, which can be quantified by imaging in vivo, leading to an alteration of cell cycle progression and caspase 3/7 activity. In summary, noninvasive imaging of E2F-1 as a common downstream regulator of cell cycle progression using the Cis-E2F-TA-LUC-IRES-TKGFP reporter system is highly attractive for evaluating the kinetics of cell cycle regulation and the effects of novel cell cycle targeting anticancer agents in vivo. [Cancer Res 2008;68(14):5932-40]
“…It has been identified to be related with a variety of human cancers including brain tumors [22]. Mathivanan et al found loss of heterozygosity and deregulated expression of RB1 in human brain tumors [23]. Fig.…”
BackgroundAccurately identifying gene regulatory network is an important task in understanding in vivo biological activities. The inference of such networks is often accomplished through the use of gene expression data. Many methods have been developed to evaluate gene expression dependencies between transcription factor and its target genes, and some methods also eliminate transitive interactions. The regulatory (or edge) direction is undetermined if the target gene is also a transcription factor. Some methods predict the regulatory directions in the gene regulatory networks by locating the eQTL single nucleotide polymorphism, or by observing the gene expression changes when knocking out/down the candidate transcript factors; regrettably, these additional data are usually unavailable, especially for the samples deriving from human tissues.ResultsIn this study, we propose the Context Based Dependency Network (CBDN), a method that is able to infer gene regulatory networks with the regulatory directions from gene expression data only. To determine the regulatory direction, CBDN computes the influence of source to target by evaluating the magnitude changes of expression dependencies between the target gene and the others with conditioning on the source gene. CBDN extends the data processing inequality by involving the dependency direction to distinguish between direct and transitive relationship between genes. We also define two types of important regulators which can influence a majority of the genes in the network directly or indirectly. CBDN can detect both of these two types of important regulators by averaging the influence functions of candidate regulator to the other genes. In our experiments with simulated and real data, even with the regulatory direction taken into account, CBDN outperforms the state-of-the-art approaches for inferring gene regulatory network. CBDN identifies the important regulators in the predicted network: 1. TYROBP influences a batch of genes that are related to Alzheimer’s disease; 2. ZNF329 and RB1 significantly regulate those ‘mesenchymal’ gene expression signature genes for brain tumors.ConclusionBy merely leveraging gene expression data, CBDN can efficiently infer the existence of gene-gene interactions as well as their regulatory directions. The constructed networks are helpful in the identification of important regulators for complex diseases.
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