The P53-induced Gene-6 (proline Oxidase) Mediates Apoptosis Through a Calcineurin-dependent Pathway: Potential Role in Human Cancer

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ProQuest, 2006 - 154 pages
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Proline oxidase is a p53-induced redox gene that can mediate apoptosis in distinct tumor cells by generating reactive oxygen species (ROS). Initially, evidence is provided implicating a role for praline oxidase in renal carcinoma, hence its expression is reduced or absent in 8 of 12 primary renal cell carcinomas, when compared to their healthy tissue counterparts. Two renal cell carcinomas (T4 and T7) out of the 12 tested, expressed modest or no expression at all of proline oxidase. T4 and T7 expressed p53s that were incapable of inducing proline oxidase when compare to the wild type p53 isolated from normal renal tissue. When sequencing T4 and T7, it was found that T4 contained a double transition mutation at amino acid residues 125 (Ala to Thr) and 193 (Arg to His), and T7 has a single transition mutation at amino acid 149 (Ser to Phe). Overexpression of proline oxidase induced the formation of ROS and mediated apoptosis in the 786-0 renal cell carcinoma cell line. A proline oxidase antisense vector inhibited p53-induced overexpression of proline oxidase, release of cytochrome c from mitochondria, and apoptosis in 786-0 renal carcinoma cells. After that, proline oxidase is reported as a downstream effector in p53-mediated activation of the calcium/calmodulin-dependent phosphatase calcineurin in lung, kidney, colon, and ovarian carcinoma cells. The p53- and proline oxidase-activation of calcineurin was indirectly detected by upregulation of the nuclear factor of activated T cells (NFAT), a well known indicator of activated calcineurin. Both praline oxidase- and p53-induced activation of NFAT were susceptible to the calcineurin inhibitors cyclosporin A and FK-506, to scavengers of ROS, and to inhibitors of calcium mobilization. A proline oxidase antisense vector inhibited the ability of p53 to induce the overexpression of proline oxidase, activate Calcineurin, and provoke apoptosis. Furthermore, T4 and T7 mutant p53 proteins were defective in inducing praline oxidase expression and in upregulating Calcineurin. Calcineurin and calcium mobilization inhibitors obliterated proline oxidase-mediated apoptosis and reduced p53-induced apoptosis. With the intention of induce wild type p53 in colon and ovarian carcinoma cells the anticancer genotoxic agent etoposide was used. Etoposide presence activated p53, proline oxidase, Calcineurin upregulation, and induced apoptosis. Calcineurin activation and induction of apoptosis stimulated by etoposide was distinctly suppressed by FK-506 calcineurin inhibitor. As a whole, it is proposed that proline oxidase is a downstream effector in p53-mediated apoptosis; that its modified expression can play a part in the development of renal carcinomas; that proline oxidase intervenes in p53-induced apoptosis through the generation of proline-dependent ROS, thus mobilizing calcium and activating calcineurin; that the initiation of calcineurinreguiated transcription factor pathways by p53 and proline oxidase might affect gene expression events important to p53 regulation of cell growth and apoptosis. The existence of proline oxidase in mitochondria, a key organelle that regulates apoptosis, places this protein in a strategic confinement that can directly have an effect on the apoptosic pathway and thus tumorigenesis.
 

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