Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chimeric tumor suppressor-1 (CTS-1) is based on the sequence of p53 and was designed as a therapeutic tool resisting various mechanisms of p53 inactivation. We previously reported that an adenovirus expressing CTS-1 (Ad-CTS-1) has superior cell death-inducing activity in glioma cells compared with wild-type p53. Here, we used cDNA microarrays to detect changes in gene expression preferentially induced by Ad-CTS-1. The putative serine threonine kinase, PCTAIRE3, and the quinone oxireductase, PIG3, were strongly induced by Ad-CTS-1 compared with wild-type p53. An adenoviral vector encoding PCTAIRE3 (Ad-PCTAIRE3) induced growth arrest and killed a minor proportion of the glioma cells. Ad-PIG3 alone affected neither growth nor viability. However, coinfection with Ad-PCTAIRE3 and Ad-PIG3 resulted in enhanced growth inhibition compared with Ad-PCTAIRE3 infection alone. Ad-CTS1, Ad-PCTAIRE3 or Ad-PIG3 induced the formation of free reactive oxygen species (ROS). However, the prevention of ROS formation induced by Ad-PCTAIRE3 and Ad-CTS-1 did not block growth arrest and cell death, suggesting that ROS formation is not essential for these effects. Altogether, these data identify PCTAIRE3 as one novel growth-inhibitory and death-inducing p53 response gene and suggest that changes in the expression of specific target genes contribute to the superior anti-glioma activity of CTS-1.
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PMID:PCTAIRE3: a putative mediator of growth arrest and death induced by CTS-1, a dominant-positive p53-derived synthetic tumor suppressor, in human malignant glioma cells. 1627 48

The identification of genes involved in carcinogenesis and tumor progression is of great interest since these genes might be feasible as candidates for new tumor-targeted therapy strategies. Chimeric tumor suppressor-1 (CTS-1), an artificial synthetic variant of p53, resists common p53 inactivation and could therefore be defined as a dominant-positive p53 variant. Overexpression of CTS-1 induces caspase-independent cell death. We used whole-genome microarray expression analysis in a parental (229(P)) and a CTS-1-resistant glioma cell line (229(Res)) to analyze alterations in gene expression in Ad-CTS-1-infected and in uninfected parental and resistant cells. In total, 700 genes were differentially expressed in infected and 313 genes in uninfected 229(Res) versus 229(P) cells. Ingenuity Pathway Analysis determined a variety of differentially expressed genes in Ad-CTS-1-infected cells that were members of intracellular networks with central tumor-involved players such as nuclear factor-kappaB (NFkappaB), protein kinase B/AKT or transforming growth factor-beta. Here we focused on the function of NFkappaB in Ad-CTS-1-mediated cell death in glioma. NFkappaB was activated in Ad-CTS-1-infected 229(P) but not 229(Res) cells. NFkappaB activation was accompanied by the induction of cell death in parental cells. Inhibition of NFkappaB activity by expression of an IkappaB super repressor or upregulation of the NFkappaB-linked gene Bex protected parental cells to Ad-CTS-1-induced cell death, whereas knockdown of Bex sensitized both parental and resistant cells. Taken together, these data suggest that activation of the normally antiapoptotic protein NFkappaB does not always necessarily protect cells from apoptosis but, in the glioma cell lines tested so far, and in an environment where p53 is constitutively active, also leads to the induction of cell death.
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PMID:Gene expression profile in a glioma cell line resistant to cell death induced by the chimeric tumor suppressor-1 (CTS-1), a dominant-positive variant of p53--the role of NFkappaB. 2001 65