ARF Promotes MDM2 Degradation and Stabilizes p53: ARF-INK4a Locus Deletion Impairs Both the Rb and p53 Tumor Suppression Pathways

@article{Zhang1998ARFPM,
  title={ARF Promotes MDM2 Degradation and Stabilizes p53: ARF-INK4a Locus Deletion Impairs Both the Rb and p53 Tumor Suppression Pathways},
  author={Yanping Zhang and Yue Xiong and Wendell G Yarbrough},
  journal={Cell},
  year={1998},
  volume={92},
  pages={725-734}
}
The INK4a-ARF locus encodes two unrelated proteins that both function in tumor suppression. p16INK4 binds to and inhibits the activity of CDK4 and CDK6, and ARF arrests the cell cycle in a p53-dependent manner. We show here that ARF binds to MDM2 and promotes the rapid degradation of MDM2. This interaction is mediated by the exon 1beta-encoded N-terminal domain of ARF and a C-terminal region of MDM2. ARF-promoted MDM2 degradation is associated with MDM2 modification and concurrent p53… Expand
ARF promotes accumulation of retinoblastoma protein through inhibition of MDM2
TLDR
This study demonstrates that ARF plays a direct role in regulation of Rb and suggests that inactivation of ARF may lead to defects in both p53 and Rb pathways in human cancer development. Expand
Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2.
TLDR
Overexpression of p19(ARF) in wild type or ARF-null mouse embryo fibroblasts increases the half-life of p53 from 15 to approximately 75 min, correlating with an increased p53-dependent transcriptional response and growth arrest. Expand
Modific ation of mdmx by ubiquitination and sumoylation
The p53 tumor suppressor is regulated by MDM2-mediated ubiquitination and degradation. Mitogenic signals activate p53 by induction of ARF expression, which inhibits p53 ubiquitination by MDM2. RecentExpand
ARF-BP1/Mule Is a Critical Mediator of the ARF Tumor Suppressor
TLDR
It is revealed that ARF-BP1 is a critical mediator of both the p53-independent and p 53-dependent tumor suppressor functions of ARF, and may serve as a potential target for therapeutic intervention in tumors regardless of p53 status. Expand
P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2.
  • W. Tao, A. Levine
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 1999
TLDR
It is shown here that coexpression of p19(ARF) blocks the nucleo-cytoplasmic shuttling of Mdm2, suggesting that MDM2 might be exported through the nucleolus and p19-ARF could inhibit the nuclear export of Mdn2 by tethering Mdm1 in the nucleolia. Expand
Ribosomal Protein L11 Negatively Regulates Oncoprotein MDM2 and Mediates a p53-Dependent Ribosomal-Stress Checkpoint Pathway
TLDR
It is shown that the functional consequence of L11-HDM2 association results in the prevention of HDM2-mediated p53 ubiquitination and degradation, subsequently restoring p53-mediated transactivation, accumulating p21 protein levels, and inducing a p 53-dependent cell cycle arrest by canceling the inhibitory function of HDm2. Expand
Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53.
TLDR
The results suggest an ARF-regulated MDM2-dependent p53 stabilization and link the human tumor-associated mutations in ARF with a functional alteration. Expand
The Ink4a Tumor Suppressor Gene Product, p19Arf, Interacts with MDM2 and Neutralizes MDM2's Inhibition of p53
TLDR
It is shown that p19Arf potently suppresses oncogenic transformation in primary cells and that this function is abrogated when p53 is neutralized by viral oncoproteins and dominant-negative mutants but not by the p53 antagonist MDM2. Expand
Human tumor suppressor ARF impedes S-phase progression independent of p53.
TLDR
It is shown that ARF colocalizes with DNA replication protein A (RPA32) and that overexpression of ARF reduces the rate of DNA synthesis resulting in accumulation of an S-phase cell population and that Impediment ofDNA synthesis by ARF can occur and becomes more evident in the absence of p53. Expand
Defining the Role of CtBP2 in p53-Independent Tumor Suppressor Function of ARF: A Dissertation
TLDR
Evidence suggests that ARF exerts both p53dependent and p53-independent tumor suppressor activity, and the antiapoptotic, metabolically regulated, transcriptional corepressor C-terminal binding protein 2 (CtBP2) has been identified as a specific target of ARF’s p53independent tumor suppression. Expand
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