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

  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 Gray Yarbrough},

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ARF promotes accumulation of retinoblastoma protein through inhibition of MDM2

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.

Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2.

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.

Modific ation of mdmx by ubiquitination and sumoylation

Evidence is presented that MDM2 promotes MDMX ubiquitination and degradation by the proteasomes, and this effect is stimulated by ARF and correlates with the ability of ARF to bindMDM2.

P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2.

  • W. TaoA. Levine
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
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.

Ribosomal Protein L11 Negatively Regulates Oncoprotein MDM2 and Mediates a p53-Dependent Ribosomal-Stress Checkpoint Pathway

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.

Defining the Role of CtBP2 in p53-Independent Tumor Suppressor Function of ARF: A Dissertation

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.

Human tumor suppressor ARF impedes S-phase progression independent of p53.

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.



Mdm2 promotes the rapid degradation of p53

It is proposed that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.

Regulation of p53 stability by Mdm2

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.

Repression of p53-mediated transcription by MDM2: a dual mechanism.

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.

Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential.

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.

mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein

It is suggested that mdm-2 binding to p53 and the resultant inhibition of p53 transcription functions are critical for reversing p53-mediated cell cycle arrest and the apoptosis functions.

Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway.

It is demonstrated thatMDM2 overexpression can inhibit p53 function in a known physiologic pathway and is consistent with the hypothesis that MDM2 mayfunction in a "feedback loop" mechanism with p53, possibly acting to limit the length or severity of the p53-mediated arrest following DNA damage.

Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53

Results suggest that a critical role of Mdm2 in development is the regulation of p53 function, and that mice deficient for both MDM2 and p53 develop normally and are viable.

Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53

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.