Antizyme1 mediates AURKAIP1-dependent degradation of Aurora-A

Lim, Sai‐Kiang; Gopalan, Ganesan

doi:10.1038/sj.onc.1210482

Cited by 72 publications

(63 citation statements)

References 37 publications

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“…However, it was suggested recently that Az might exert its antiproliferative effect not only through targeting ODC to ubiquitin-independent degradation and to inhibiting polyamine uptake but also by stimulating degradation of the growth-regulating proteins cyclin D1, Aurora-A, and ⌬Np73, which do not belong to polyamine metabolism (23)(24)(25). However, in these studies, the ability of Az to stimulate the degradation of these proteins was not compared with its ability to stimulate ODC degradation.…”

Section: Resultsmentioning

confidence: 69%

“…However, several recent studies put forward an alternative possibility, suggesting that Az might also inhibit cell proliferation by targeting to ubiquitin-independent degradation growth-regulating proteins that do not belong to the cellular polyamine metabolic pathway. These include Smad1, a key transducer of the bone morphogenetic proteins (20 -22); the cell cycle regulators cyclin D1 and Aurora-A (23,24); and the anti-apoptotic N-terminally truncated form of p73 (⌬Np73) (25).…”

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confidence: 99%

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Antizyme Affects Cell Proliferation and Viability Solely through Regulating Cellular Polyamines

Bercovich

Snapir²,

Keren-Paz

et al. 2011

Journal of Biological Chemistry

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Background: Antizyme is a regulator of cell proliferation, inhibiting this process when overexpressed. Results: Antizyme overexpression does not attenuate cell proliferation and viability in cells whose polyamine supply is secured. Conclusion: Antizyme affects cell proliferation and viability only by modulating polyamine metabolism. Significance: This result emphasizes the functional relationship of antizyme to cellular polyamine metabolism.

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Section: Resultsmentioning

confidence: 69%

mentioning

confidence: 99%

Antizyme Affects Cell Proliferation and Viability Solely through Regulating Cellular Polyamines

Bercovich

Snapir²,

Keren-Paz

et al. 2011

Journal of Biological Chemistry

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“…Az has been shown to degrade several cell-cycle regulatory proteins, including cyclin D1, Smad1 and Aurora A kinase, as well as Mps1, a protein that regulates centrosome (e) Schematic illustrates the proposed mechanism by which genotoxic stresses can induce the degradation of anti-apoptotic DNp73 by activating c-Jun, FosB and JunB. Upon stress, these three AP-1 family members are induced and inhibit the expression of the polyamine catabolic enzyme paox, resulting in the eventual increase in the expression of Az1(p), which leads to the degradation of DNp73, and consequently, chemosensitizes to genotoxic drugs duplication, [32][33][34][35] supporting its role as an inhibitor of tumor cell proliferation and transformation. The expression of Az is tightly controlled at the post-transcriptional level by a þ 1 frameshift translation mechanism, which is regulated by the polyamine biosynthesis pathway.…”

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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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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“…The level of Aurora-A protein is tightly cell cycle regulated; it is degraded rapidly toward the end of mitosis and before cytokinesis in mammalian cells (6)(7)(8)27). Previous studies have revealed that Aurora-A protein is a short-lived protein that has a rapid turnover rate with a half-life of ∼2 hours (6).…”

Section: Discussionmentioning

confidence: 99%

Aurora-A Overexpression in Mouse Liver Causes p53-Dependent Premitotic Arrest during Liver Regeneration

Yang

Chou

et al. 2009

Molecular Cancer Research

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Aurora-A, a serine-threonine kinase, is frequently overexpressed in human cancers, including hepatocellular carcinoma. To study the phenotypic effects of Aurora-A overexpression on liver regeneration and tumorigenesis, we generated transgenic mice overexpressing human Aurora-A in the liver. The overexpression of Aurora-A after hepatectomy caused an earlier entry into S phase, a sustaining of DNA synthesis, and premitotic arrest in the regenerating liver. These regenerating transgenic livers show a relative increase in binuclear hepatocytes compared with regenerating wild-type livers; in addition, multipolar segregation and trinucleation could be observed only in the transgenic hepatocytes after hepatectomy. These results together suggest that defects accumulated after first round of the hepatocyte cell cycle and that there was a failure to some degree of cytokinesis. Interestingly, the p53-dependent checkpoint was activated by these abnormalities, indicating that p53 plays a crucial role during liver regeneration. Indeed, the premitotic arrest and abnormal cell death, mainly necrosis, caused by Aurora-A overexpression were genetically rescued by p53 knockout. However, trinucleation of hepatocytes remained in the regenerating livers of the transgenic mice with a p53 knockout background, indicating that the abnormal mitotic segregation and cytokinesis failure were p53 independent. Moreover, overexpression of Aurora-A in transgenic liver led to a low incidence (3.8%) of hepatic tumor formation after a long latency period. This transgenic mouse model provides a useful system that allows the study of the physiologic effects of Aurora-A on liver regeneration and the genetic pathways of Aurora-A-mediated tumorigenesis in liver.

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Antizyme1 mediates AURKAIP1-dependent degradation of Aurora-A

Cited by 72 publications

References 37 publications

Antizyme Affects Cell Proliferation and Viability Solely through Regulating Cellular Polyamines

Antizyme Affects Cell Proliferation and Viability Solely through Regulating Cellular Polyamines

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

Aurora-A Overexpression in Mouse Liver Causes p53-Dependent Premitotic Arrest during Liver Regeneration

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