Journal ArticleDOI
Inactivation of the p53 pathway in retinoblastoma
Nikia A. Laurie,Stacy L. Donovan,Chie Schin Shih,Jiakun Zhang,Nicholas Mills,Christine E. Fuller,Amina F A S Teunisse,Suzanne Lam,Yolande F. M. Ramos,Adithi Mohan,Dianna A. Johnson,Matthew W. Wilson,Carlos Rodriguez-Galindo,Micaela Quarto,Sarah Francoz,Susan M. Mendrysa,R. Kiplin Guy,Jean-Christophe Marine,Aart G. Jochemsen,Michael A. Dyer +19 more
TLDR
It is shown that the tumour surveillance pathway mediated by Arf, MDM2, MDMX and p53 is activated after loss of RB1 during retinogenesis, providing evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought.Abstract:
Most human tumours have genetic mutations in their Rb and p53 pathways, but retinoblastoma is thought to be an exception. Studies suggest that retinoblastomas, which initiate with mutations in the gene retinoblastoma 1 (RB1), bypass the p53 pathway because they arise from intrinsically death-resistant cells during retinal development. In contrast to this prevailing theory, here we show that the tumour surveillance pathway mediated by Arf, MDM2, MDMX and p53 is activated after loss of RB1 during retinogenesis. RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumour progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. Our data provide evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought. In addition, they support the idea that MDMX is a specific chemotherapeutic target for treating retinoblastoma.read more
Citations
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Journal ArticleDOI
MDM2, MDMX and p53 in oncogenesis and cancer therapy.
TL;DR: This Review highlights the progress made and pitfalls encountered as the field continues to search for MDM-targeted antitumour agents.
Journal ArticleDOI
Awakening guardian angels: drugging the p53 pathway
TL;DR: Several original approaches to drug discovery that could have wide applications to drug development are being used, including molecules that activate p53 by blocking protein–protein interactions with MDM2 and p53-binding molecules that can rescue the function of certain p53 mutants.
Journal ArticleDOI
The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression
TL;DR: This review focuses on the cell-cycle arrest and apoptosis functions of p53, their roles in tumor suppression, and the regulation of cell fate decision after p53 activation.
Journal ArticleDOI
Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition
Sanjeev Shangary,Dongguang Qin,Donna McEachern,Meilan Liu,Rebecca Miller,Su Qiu,Zaneta Nikolovska-Coleska,Ke Ding,Guoping Wang,Jianyong Chen,Denzil Bernard,Jian Zhang,Yipin Lu,Qingyang Gu,Rajal B. Shah,Kenneth J. Pienta,Xiaolan Ling,Sanmao Kang,Ming Guo,Yi Sun,Dajun Yang,Shaomeng Wang +21 more
TL;DR: MI-219 stimulates rapid but transient p53 activation in established tumor xenograft tissues, resulting in inhibition of cell proliferation, induction of apoptosis, and complete tumor growth inhibition.
Journal ArticleDOI
Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy.
Sanjeev Shangary,Shaomeng Wang +1 more
TL;DR: This review will highlight recent advances in the design and development of small-molecule inhibitors of the MDM2-p53 interaction as new cancer therapies and highlight analogs of MI-219 and Nutlin-3.
References
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TL;DR: In this article, the authors identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts.
Journal ArticleDOI
Cancer genes and the pathways they control.
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Journal Article
Participation of p53 Protein in the Cellular Response to DNA Damage
TL;DR: A role for the wild-type p53 protein in the inhibition of DNA synthesis that follows DNA damage is suggested and a new mechanism for how the loss of wild- type p53 might contribute to tumorigenesis is suggested.