The ARF/p53 pathway

Sherr, Charles J.; Weber, Jason D.

doi:10.1016/s0959-437x(99)00038-6

Cited by 602 publications

(424 citation statements)

References 45 publications

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“…Since inhibition was generally incomplete, other factors may still be necessary to complement p53 activity, such as p14Arf. 37,38 Mdm2, an antagonist of p53 function and E3 ubiquitin ligase that promotes p53 degradation, 16 may reduce the efficiency of the pCL and pCLPG systems, contributing to the incomplete inhibition observed here. The possible role of the p53 family members, p63 and p73, in the function of the pCLPG system have not yet been addressed.…”

Section: Discussionmentioning

confidence: 94%

A novel gene transfer strategy that combines promoter and transgene activities for improved tumor cell inhibition

2005

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Typically, gene transfer strategies utilize a promoter/transgene arrangement that treat these elements independently and do not offer any interplay between them. Our goal was to establish a promoter/transgene combination that would result in improvement in both expression and therapeutic effect by utilizing the transcriptional properties of p53 to drive its own expression as well as act as a tumor suppressor. The pCL retroviral system was modified in the U3 region of the 3 0 LTR by the addition of a p53-responsive sequence (the PG element), creating the pCLPG system. Upon reverse transcription, the 5 0 LTR is converted, as shown here, to a p53-dependent promoter. We also show, using a temperature-sensitive model, that the pCLPG system could be driven by p53 encoded within the virus construct and expression was modulated depending on the p53 phenotype, demonstrating a regulatory feedback loop. Moreover, the pCLPG system was shown to express the transgene at a higher level and to inhibit tumor cell proliferation more robustly than the original pCL system. This novel system employs the transgene to serve two purposes, drive viral expression and inhibit tumor cell proliferation. The pCLPG vectors represent a new gene transfer strategy of synergizing the promoter and transgene activities. Cancer Gene Therapy (2005) 12, 935-946.

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Section: Discussionmentioning

confidence: 94%

A novel gene transfer strategy that combines promoter and transgene activities for improved tumor cell inhibition

2005

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“…This became very clear when a new tumour suppressor protein was identified, p14ARF, which is induced by activation of E2F and acts as an upstream activator of p53 (Bates et al, 1998;Palmero et al, 1998). p14ARF can bind to Mdm2 and sequester it in the nucleolus of the cell keeping it physically away from p53 thereby preventing p53's degradation (Sherr and Weber, 2000). The result of Mdm2 neutralization by p14ARF is that p53 protein levels will rise and subsequently cause cell cycle arrest and apoptosis.…”

Section: Cell Cycle Control In Cancer Cellsmentioning

confidence: 99%

ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus

2002

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Accumulated knowledge in the molecular processes of tumour development combined with the availability of genetically modified viruses resemble the basis for new promising cancer therapeutics. The main advantages of employing replicationcompetent viruses are achievement of tumour selective killing and amplification of their oncolytic potential within the tumour mass. In this review, we describe the development of ONYX-015, one of the first and most advanced replication-competent viruses for cancer therapy. We discuss the molecular biology of this therapeutic approach and the interesting results obtained with this virus in clinical trials.

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“…It is already clear that regulation of Hdm2 activity at the post-translational level is critically important for the control of its function, with Hdm2 phosphorylation and protein:protein interactions being a critical point of convergence for both stress-and survival-induced signalling pathways (Meek and Knippschild, 2003;Michael and Oren, 2003). Of particular note is the stress-induced increase in Hdm2 protein turnover that contributes to the activation of p53 following DNA damage (Stommel and Wahl, 2004), the phosphorylation of Hdm2 by Akt kinase, which promotes the accumulation of Hdm2 in the nucleus and is an important component of the effects of pro-survival factors such as Insulin-like Growth Factor-1 (Shaulian et al, 1997;Mayo and Donner, 2001;Ashcroft et al, 2002;Feng et al, 2004), and the induction of the Hdm2 antagonist, p14 ARF by oncogenic stress (Stott et al, 1998;Sherr and Weber, 2000).…”

Section: Introductionmentioning

confidence: 99%

GC-selective DNA-binding antibiotic, Mithramycin A, reveals multiple points of control in the regulation of Hdm2 protein synthesis

2006

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The primary role of the Hdm2/Mdm2 oncoprotein is to regulate the levels and activity of the transcription factor p53. Hdm2 synthesis is itself tightly controlled and, as demonstrated by a recently described SNP (SNP309) in the hdm2-P2 promoter, minor variations in Hdm2 expression have phenotypic consequences on radiation sensitivity and cancer predisposition. To further define mechanisms regulating Hdm2 expression, we have investigated the effects of the GC-selective DNA-binding drug, Mithramycin A (MA) on hdm2 mRNA transcription, trafficking, and translation. Firstly we show that the constitutive hdm2-P1 promoter is inhibited by MA. We define, for the first time, the minimal sequence elements that are required for P1-promoter activity and identify those which confer MA sensitivity. Secondly, MA induces p53-dependent transcription from the hdm2-P2 promoter. Thirdly, and critically, MA also inhibits Hdm2 synthesis at the post-transcriptional level, with negative effects on hdm2 mRNA nuclear export and translation. This study highlights the complex interplay between the pathways that regulate Hdm2 protein synthesis in cancer cells, and furthermore emphasizes the export of hdm2 mRNA from the nucleus to the cytoplasm as a key point of control in this process.

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The ARF/p53 pathway

Cited by 602 publications

References 45 publications

A novel gene transfer strategy that combines promoter and transgene activities for improved tumor cell inhibition

A novel gene transfer strategy that combines promoter and transgene activities for improved tumor cell inhibition

ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus

GC-selective DNA-binding antibiotic, Mithramycin A, reveals multiple points of control in the regulation of Hdm2 protein synthesis

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