c-Jun Regulates the Stability and Activity of the p53 Homologue, p73

Toh, Wen Hong; Siddique, Monowarul Mobin; Boominathan, Lakshmanane; Lin, Kai; Sabapathy, Kanaga

doi:10.1074/jbc.m407672200

Cited by 71 publications

(84 citation statements)

References 37 publications

(62 reference statements)

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“…Immunoblot analysis was performed essentially as described. 47 Site-directed mutagenesis (SDM) and luciferase reporter assays. The -3045 to -997 paox promoter fragment was cloned into in pGL3 basic or enhancer vector (Promega, Fitchburg, WI, USA).…”

Section: Discussionmentioning

confidence: 99%

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Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

et al. 2014

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Enhanced resistance to chemotherapy has been correlated with high levels of Delta-Np73 (DNp73), an anti-apoptotic protein of the p53 tumor-suppressor family which inhibits the pro-apoptotic members such as p53 and TAp73. Although genotoxic drugs have been shown to induce DNp73 degradation, lack of mechanistic understanding of this process precludes strategies to enhance the targeting of DNp73 and improve treatment outcomes. Antizyme (Az) is a mediator of ubiquitin-independent protein degradation regulated by the polyamine biosynthesis pathway. We show here that acetylpolyamine oxidase (PAOX), a catabolic enzyme of this pathway, upregulates DNp73 levels by suppressing its degradation via the Az pathway. Conversely, downregulation of PAOX activity by siRNA-mediated knockdown or chemical inhibition leads to DNp73 degradation in an Az-dependent manner. PAOX expression is suppressed by several genotoxic drugs, via selected members of the activator protein-1 (AP-1) transcription factors, namely c-Jun, JunB and FosB, which are required for stress-mediated DNp73 degradation. Finally, chemical-and siRNA-mediated inhibition of PAOX significantly reversed the resistant phenotype of DNp73-overexpressing cancer cells to genotoxic drugs. Together, these data define a critical mechanism for the regulation of DNp73 abundance, and reveal that inhibition of PAOX could widen the therapeutic index of cytotoxic drugs and overcome DNp73-mediated chemoresistance in tumors.

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Section: Discussionmentioning

confidence: 99%

“…Luciferase assays were performed as described. 47 Potential AP-1-binding sites were found using TESS (Transcription Element Search System online software). SDM of the AP-1 sites P1 and P2 were carried out as described.…”

Section: Discussionmentioning

confidence: 99%

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

et al. 2014

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“…The transacting factors and mechanism through which JNK enzymes stabilize mPGES-1 mRNA in cardiomyocytes remains to be defined. In addition to regulating mPGES-1 mRNA stability, JNK enzymes may also participate in the regulation of mPGES-1 mRNA translation and/or the regulation of mPGES-1 protein stability, as JNK enzymes have been shown to stabilize many proteins (20,22,38,39).…”

Section: Discussionmentioning

confidence: 99%

c-Jun N-terminal Kinase-mediated Stabilization of Microsomal Prostaglandin E2 Synthase-1 mRNA Regulates Delayed Microsomal Prostaglandin E2 Synthase-1 Expression and Prostaglandin E2 Biosynthesis by Cardiomyocytes

Dégousée

Angoulvant

Fazel

et al. 2006

Journal of Biological Chemistry

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“…These results also correlated with the known roles of these proteins in apoptosis. Because JNK activation regulates stress-induced apoptosis, its downstream target c-Jun is important for p73 activation (29), and a recent report suggests the involvement of JNK in EGCG-induced apoptosis (26), we next focused on JNK activation. To further confirm that SHP-2 negatively regulates EGCG-induced JNK phosphorylation, we analyzed JNK activation in the rescued clones.…”

Section: Jnk Activation Is Dispensable For Apoptosis and P53 Target Genementioning

confidence: 99%

SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG

Amin¹,

Thakur²,

Paul³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Green tea polyphenol, epigallocatechin-3-gallate (EGCG) differentially regulates the cellular growth of cancer cells in a p53-dependent manner through apoptosis and/or cell cycle arrest. In an effort to further elucidate the mechanism of differential growth regulation by EGCG, we have investigated the role of the tyrosine phosphatase, SHP-2. Comparing the responses of mouse embryonic fibroblasts (MEFs), expressing either WT or functionally inactive/truncated SHP-2, we find that inactivation of SHP-2 remarkably sensitizes cells to EGCG-mediated killing. MEFs lacking functional SHP-2 undergo massive apoptosis upon treatment with EGCG. By comparing gene expression profiles, we have identified a set of transcriptional targets of p53 that are differentially modulated in cells undergoing apoptosis. Western blot and real-time PCR analyses of a select group of genes further confirm that the expression is SHP-2-dependent. Similar observations were made in MEFs lacking p53, confirming that the expression of these ''p53 target genes'' is p53-independent. In addition, EGCG treatment induced the expression of p73 mRNA and protein in both cell types, but not p63. Inactivation of p73 in cells expressing nonfunctional SHP-2 markedly inhibited apoptosis and p53 target gene expression. Although phosphorylation of JNK is differentially regulated by SHP2, it was found to be dispensable for EGCG-induced apoptosis and p53 target gene expression. Our results have identified SHP-2 as a negative regulator of EGCG-inducedapoptosis and have identified a subset of p53 target genes whose expression is paradoxically not mediated by p53 but by one of its family members, p73.green tea ͉ MAPK pathway ͉ mouse embryonic fibroblasts ͉ transcriptional activation

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c-Jun Regulates the Stability and Activity of the p53 Homologue, p73

Cited by 71 publications

References 37 publications

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

c-Jun N-terminal Kinase-mediated Stabilization of Microsomal Prostaglandin E2 Synthase-1 mRNA Regulates Delayed Microsomal Prostaglandin E2 Synthase-1 Expression and Prostaglandin E2 Biosynthesis by Cardiomyocytes

SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG

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