TRIAD1 inhibits MDM2‐mediated p53 ubiquitination and degradation

Abstract

Edited by Varda RotterKeywords: p53 MDM2 Ubiquitination TRIAD1 a b s t r a c t Murine double minute (MDM2) is an E3 ligase that promotes ubiquitination and degradation of tumor suppressor protein 53 (p53). MDM2-mediated regulation of p53 has been investigated as a classical tumorigenesis pathway. Here, we describe TRIAD1 as a novel modulator of the p53-MDM2 axis that induces p53 activation by inhibiting its regulation by MDM2. Ablation of TRIAD1 attenuates p53 levels activity upon DNA damage, whereas ectopic expression of TRIAD1 promotes p53 stability by inhibiting MDM2-mediated ubiquitination/degradation. Moreover, TRIAD1 binds to the C-terminus of p53 to promote its dissociation from MDM2. These results implicate TRIAD1 as a novel regulatory factor of p53-MDM2. Structured summary of protein interactions:p53 physically interacts with Mdm2 and Triad1 by anti tag coimmunoprecipitation (View Interaction: 1, 2, 3) Mdm2 physically interacts with Triad1 by anti tag coimmunoprecipitation (View interaction) p53 physically interacts with Mdm2 by anti tag coimmunoprecipitation (View interaction) Triad1 binds to p53 by pull down (View interaction) Mdm2 physically interacts with p53 by anti tag coimmunoprecipitation (View interaction) p53 physically interacts with Triad1 by anti tag coimmunoprecipitation (View interaction)

TRIAD1 Is a Novel Transcriptional Target of p53 and Regulates Nutlin‐3a‐Induced Cell Death

“…In addition, we found that TRIAD1 induces apoptosis in p53 WT cancer cells but not in null p53 (p53 null ) cells [Jung et al, ]. Later studies revealed that TRIAD1 directly interacts with p53 and that this interaction stabilizes p53 rather than inducing its ubiquitination [Bae et al, ], similar to the effect of TRIAD1 on Gfi1. Furthermore, we found that TRIAD1 inhibits the interaction between p53 and MDM2, an ubiquitin E3 ligase that targets p53 [Bae et al, ].…”

“…The plasmids expressing TRIAD1 and p53 (pEGFP‐C1‐TRIAD1 and pcDNA3.1‐HA‐p53, respectively) were generated as previously described [Bae et al, ]. Mutant p53 expression construct (C135Y p53) was kindly provided by Dr. Carl G Maki (University of Chicago, Chicago, IL).…”

“…Later studies revealed that TRIAD1 directly interacts with p53 and that this interaction stabilizes p53 rather than inducing its ubiquitination [Bae et al, ], similar to the effect of TRIAD1 on Gfi1. Furthermore, we found that TRIAD1 inhibits the interaction between p53 and MDM2, an ubiquitin E3 ligase that targets p53 [Bae et al, ]. Notably, cotransfection of TRIAD1 and p53 stabilizes p53 in p53 −/− MEFs but not in p53 −/− mdm2 −/− MEFs, indicating that TRIAD1 interferes with the functional interaction between MDM2 and p53 [Bae et al, ].…”

“…Furthermore, we found that TRIAD1 inhibits the interaction between p53 and MDM2, an ubiquitin E3 ligase that targets p53 [Bae et al, ]. Notably, cotransfection of TRIAD1 and p53 stabilizes p53 in p53 −/− MEFs but not in p53 −/− mdm2 −/− MEFs, indicating that TRIAD1 interferes with the functional interaction between MDM2 and p53 [Bae et al, ].…”

Triad1 regulates the expression and distribution of EHD1 contributing to the neurite outgrowth of neurons after spinal cord injury

“…22 TRIADs play an important role in a large range of cellular events from intracellular to intercellular signal transduction. 26 As we all know, p53 is a key point in the nerve growth factor, (NGF)mediated neurite outgrowth of PC12 cells via regulating high-affinity NGF receptor TrkA levels. A recent research showed Triad1 played a role in membrane trafficking and its mutant causes the wrong accumulation of receptors, such as the growth hormone receptor and the epidermal growth factor receptor, in endosomes and at the plasma membrane.…”