Apoptosis of tumoral and nontumoral lymphoid cells is induced by both mdm2 and p53 antisense oligodeoxynucleotides

Abstract

Following stress signals, the p53 tumor suppressor protein plays a critical role in regulation of cell proliferation, mainly through induction of growth arrest or apoptosis. Therefore, this protein needs to be strictly regulated and numerous studies have shown that the MDM2 protein is an essential element for p53 regulation in normal cells and, most importantly, that overexpression of MDM2 is responsible for p53 inactivation in various types of tumors. A previous study showed that this is the case in some Burkitt lymphoma (BL) cell lines, where enhanced translation of mdm2 messenger RNA results in overexpression of the protein that complexes and inactivates wild-type p53. To further investigate the role of the p53/MDM2 complex in these BL cells, as well as in other lymphoid cells that do not overexpress MDM2, this study used antisense oligodeoxynucleotides directed either against mdm2 or against p53. Results show that the mdm2 antisense oligodeoxynucleotide induces apoptosis of cells that express a high or low level of MDM2 protein, only if they contain wild-type p53. Moreover, apoptosis is independent of the accumulation of p53 following mdm2 antisense treatment. Finally, the p53 antisense oligodeoxynucleotide, which inhibits the expression of wild-type p53, also induces a decrease of the MDM2 level in cells, whether or not they overexpress this protein, and causes apoptosis of these cells. These results indicate that decreasing the MDM2 protein level by directly or indirectly targeting its biosynthesis is a potent tool for the induction of apoptosis.

Essential Role for c-Jun N-Terminal Kinase 2 in Corneal Epithelial Response to Desiccating Stress

“…10,12,20,28 The activation of MAPK p38 alone has been shown to induce expression of MMP-1 and -3 in an activator protein 1–independent manner by stabilizing the corresponding mRNAs in human skin fibroblasts. 29 To confirm the relative roles of JNK1 and JNK2 in the corneal epithelial stress response in vivo, we compared corneal epithelial barrier function and smoothness, as well as production of MMPs and cornified envelope precursors, following 5 days of experimental desiccation in JNK1 and JNK2 gene–deficient and wild-type C57BL/6 strains.…”

TP53 in hematological cancer: Low incidence of mutations with significant clinical relevance

“…Primary attempts were directed at antisense therapies. For example, it was observed that both antisense oligonucleotides to the mdm2 and p53 in lymphoblastoid cell line induced apoptosis in these cells only if they expressed wild-type p53 [Capoulade et al, 2001]. Cotter [1999] reviewed the potential use of antisense therapy in hematologic malignancies.…”

Pervasive and Dynamic Transcription Initiation inSaccharomyces cerevisiae

“…Accurate transcription initiation is vital to ensure the proper expression and function of these genes (Smale and Kadonaga 2003). Mis-regulation of transcription initiation has been found to be associated with a broad range of human diseases, such as breast cancer, diabetes, kidney failure and Alzheimer's disease (Arrick et al 1991;Romeo et al 1993;Capoulade et al 2001;Sobczak and Krzyzosiak 2002;Mihailovich et al 2007). In this regard, accurate identification of TSSs and characterization of their regulated activities are essential for obtaining fundamental insights into regulatory mechanisms that determine the location and activities of transcription initiation.…”