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ABSTRACT: The Murine Double Minute 2 (MDM2) protein is a key regulator of cell proliferation and apoptosis that acts primarily by inhibiting the p53 tumor suppressor. Similarly, the PI3-Kinase (PI3K)/AKT pathway is critical for growth factor-mediated cell survival. Additionally, it has been reported that AKT can directly phosphorylate and activate MDM2. In this study, we show that IGF-1 up-regulates MDM2 protein levels in a PI3K/AKT-dependent manner. Inhibition of mTOR by rapamycin or expression of a dominant negative eukaryotic initiation factor 4E binding protein 1 (4EBP1) mutant protein, as well as ablation of eukaryotic initiation factor 4E (eIF4E), efficiently abolishes IGF-1-mediated up-regulation of MDM2. In addition, we show that rapamycin effectively inhibits MDM2 expression and sensitizes cancer cells to chemotherapy. Taken together, this study reveals a novel mechanism by which IGF-1 activates MDM2 via the mTOR pathway, and that pharmacologic inhibition of mTOR combined with chemotherapy may be more effective in treatment of a subset of cancers harboring increased MDM2 activation.
PLoS ONE 01/2013; 8(4):e63179. · 4.09 Impact Factor
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ABSTRACT: The p53-related protein p63 has pleiotropic functions, including cell proliferation, survival, apoptosis, differentiation, senescence, and aging. The p63 gene is expressed as multiple isoforms that either contain an N-terminal p53-homologous transactivation domain (TAp63) or that lack this domain (ΔNp63). Multiple studies have demonstrated that p63 plays a crucial role in stratified epithelial development, and have shown the importance of p63 for maintaining proliferation potential, inducing differentiation, and preventing senescence. Additionally, much research focuses on the role of p63 in cancer progression. Clinical evidence suggests that p63 may play a role in inhibiting metastasis. Similarly, genetic mice models together with cell culture data strongly indicate that p63 deficiency may be a causative factor for metastatic spread. Moreover, the role of p63 in cancer metastasis has been shown to be greatly related to the ability of mutant p53 to promote cancer malignancy. However, there is still much confusion as to what the role of each specific isoform is. In this review, we highlight some of the major findings in the current literature regarding the role of specific p63 isoforms in development, tumorigenesis, and particularly in cancer metastasis.
Cancer Microenvironment 07/2012; 5(3):311-22.
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ABSTRACT: The p53 homologue p63 encodes multiple protein isoforms either with (TA) or without (DeltaN) the N-terminal transactivation domain. Accumulating evidence indicates that TAp63 plays an important role in various biological processes, including cell proliferation, differentiation, and apoptosis. However, how TAp63 is regulated remains largely unclear. In this study, we demonstrate that NF-kappaB induces TAp63 gene expression. The responsible elements for NF-kappaB-mediated TAp63 induction are located within the region from -784 to -296 bp in the TAp63 promoter, which contains two NF-kappaB binding sites. Ectopic expression of RelA stimulates TAp63 promoter-driven reporter activity and increases endogenous TAp63 mRNA levels. Inhibition of NF-kappaB by IkappaBalpha super-repressor or with a chemical inhibitor leads to down regulation of TAp63 mRNA expression and activity. In addition, mutations in the critical NF-kappaB-binding sites significantly abolish the effects of NF-kappaB on TAp63. Activation of NF-kappaB by TNFalpha enhances p50/RelA binding to the NF-kappaB binding sites. Furthermore, we show that an Sp1 site adjacent to the NF-kappaB sites plays a role in NF-kappaB-mediated upregulation of TAp63. Taken together, these data reveal that TAp63 is a transcriptional target of NF-kappaB, which may play a role in cell proliferation, differentiation and survival upon NF-kappaB activation by various stimuli.
Journal of Cellular Biochemistry 03/2010; 109(4):702-10. · 2.87 Impact Factor
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ABSTRACT: The p53 homologue p63 encodes multiple protein isoforms either with (TA) or without (ΔN) the N-terminal transactivation domain. Accumulating evidence indicates that TAp63 plays an important role in various biological processes, including cell proliferation, differentiation, and apoptosis. However, how TAp63 is regulated remains largely unclear. In this study, we demonstrate that NF-κB induces TAp63 gene expression. The responsible elements for NF-κB-mediated TAp63 induction are located within the region from −784 to −296 bp in the TAp63 promoter, which contains two NF-κB binding sites. Ectopic expression of RelA stimulates TAp63 promoter-driven reporter activity and increases endogenous TAp63 mRNA levels. Inhibition of NF-κB by IκBα super-repressor or with a chemical inhibitor leads to down regulation of TAp63 mRNA expression and activity. In addition, mutations in the critical NF-κB-binding sites significantly abolish the effects of NF-κB on TAp63. Activation of NF-κB by TNFα enhances p50/RelA binding to the NF-κB binding sites. Furthermore, we show that an Sp1 site adjacent to the NF-κB sites plays a role in NF-κB-mediated upregulation of TAp63. Taken together, these data reveal that TAp63 is a transcriptional target of NF-κB, which may play a role in cell proliferation, differentiation and survival upon NF-κB activation by various stimuli. J. Cell. Biochem. 109: 702–710, 2010. © 2010 Wiley-Liss, Inc.
Journal of Cellular Biochemistry 01/2010; 109(4):702 - 710. · 2.87 Impact Factor
