title: Insulin receptor tyrosine kinase substrate enhances low levels of MDM2-mediated p53 ubiquitination.
abstract: The tumor suppressor p53 controls multiple cellular functions including DNA repair, cell cycle arrest and apoptosis. MDM2-mediated p53 ubiquitination affects both degradation and cytoplasmic localization of p53. Several cofactors are known to modulate MDM2-mediated p53 ubiquitination and proteasomal degradation. Here we show that IRTKS, a novel IRSp53-like protein inhibited p53-induced apoptosis and depressed its transcription activity. IRTKS bound directly to p53 and increased p53 ubiquitination and cytoplasmic localization. Further studies revealed that IRTKS interacted with MDM2 and promoted low levels of MDM2-mediated p53 ubiquitination in vitro and in vivo. In unstressed cells with low levels of MDM2, IRTKS was found to stabilize the interaction of p53 and MDM2. In stressed cells, IRTKS dissociated from p53, and high levels of MDM2 induced by p53 activation mediate IRTKS poly-ubiquitination and subsequent proteasomal degradation. These data suggest that IRTKS is a novel regulator of p53, modulating low level of MDM2-mediated p53 ubiquitination in unstressed cells.
authors: Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors: Ke-Sheng
authors: KS
authors: Wang
authors: Gang
authors: G
authors: Chen
authors: Hai-Lian
authors: HL
authors: Shen
authors: Ting-Ting
authors: TT
authors: Li
authors: Fei
authors: F
authors: Chen
authors: Qin-Wan
authors: QW
authors: Wang
authors: Zhi-Qin
authors: ZQ
authors: Wang
authors: Ze-Guang
authors: ZG
authors: Han
authors: Xin
authors: X
authors: Zhang
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C523100:BAIAP2L1 protein, human; D008840:Microfilament Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases