The Ink4a Tumor Suppressor Gene Product, p19Arf, Interacts with MDM2 and Neutralizes MDM2's Inhibition of p53

@article{Pomerantz1998TheIT,
  title={The Ink4a Tumor Suppressor Gene Product, p19Arf, Interacts with MDM2 and Neutralizes MDM2's Inhibition of p53},
  author={Jason H. Pomerantz and Nicole Schreiber-Agus and Nanette J. Li{\'e}geois and Adam Silverman and Leila Alland and Lynda Chin and Jason Potes and Ken Chen and Irene Orlow and Han-Woong Lee and Carlos Cordon-Cardo and Ronald A. DePinho},
  journal={Cell},
  year={1998},
  volume={92},
  pages={713-723}
}
The INK4a gene encodes two distinct growth inhibitors--the cyclin-dependent kinase inhibitor p16Ink4a, which is a component of the Rb pathway, and the tumor suppressor p19Arf, which has been functionally linked to p53. Here we show 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. This finding, coupled with the observations… Expand
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References

SHOWING 1-10 OF 158 REFERENCES
Mdm2 promotes the rapid degradation of p53
TLDR
It is proposed that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal. Expand
ARF Promotes MDM2 Degradation and Stabilizes p53: ARF-INK4a Locus Deletion Impairs Both the Rb and p53 Tumor Suppression Pathways
TLDR
It is shown that ARF binds to MDM2 and promotes the rapid degradation of MDM 2, and deletion of the ARF-INK4a locus simultaneously impairs both the INK4a-cyclin D/CDK4-RB and the ARf-MDM2-p53 pathways. Expand
Interaction between the retinoblastoma protein and the oncoprotein MDM2
TLDR
Here it is shown that MDM2 interacts physically and functionally with pRB and, as with p53, inhibits pRB growth regulatory function, therefore, both p RB and p53 can be subjected to negative regulation by the product of a single cellular proto-oncogene. Expand
Regulation of p53 stability by Mdm2
TLDR
It is shown that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome-dependent degradation, which may contribute to the maintenance of low p53 concentrations in normal cells. Expand
Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential.
TLDR
It is reported that in murine cells p53 activates an internal mdm2 promoter (P2) located near the 3' end of intron 1, resulting in mRNA whose transcription starts within exon 2, effectively modulating both the amount and the nature of MDM2 polypeptides through activation of the internal P2 promoter. Expand
Repression of p53-mediated transcription by MDM2: a dual mechanism.
TLDR
Results are consistent with a model in which MDM2 represses p53-dependent transcription by a dual mechanism: a masking of the activation domain of p53 through a protein-protein interaction that additionally serves to recruitMDM2 to the promoter where it directly interferes with the basal transcription machinery. Expand
Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19 ARF
TLDR
The INK4a tumor suppressor locus encodes growth inhibitory proteins that act upstream of the retinoblastoma protein and p53, and mice lacking p19ARF but expressing functional p16INK4a develop tumors early in life. Expand
Regulation of Transcription Functions of the p53 Tumor Suppressor by the mdm-2 Oncogene
TLDR
All three functions of the p53 protein—transcriptional activation, repression and mutant protein activation—require the p 53 amino terminal domain functions and are regulated by the mdm-2 protein in a cell. Expand
Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53
TLDR
It is shown that, when expressed in Saccharomyces cerevisiae, human MDM2 inhibits human p53's ability to stimulate transcription by binding to a region that nearly coincides with the p53 acidic activation domain. Expand
Inactivation of multiple tumor-suppressor genes involved in negative regulation of the cell cycle, MTS1/p16INK4A/CDKN2, MTS2/p15INK4B, p53, and Rb genes in primary lymphoid malignancies.
It is now evident that the cell cycle machinery has a variety of elements negatively regulating cell cycle progression. However, among these negative regulators in cell cycle control, only 4 haveExpand
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