title: TBP-like Protein (TLP) Disrupts the p53-MDM2 Interaction and Induces Long-lasting p53 Activation.
abstract: Stress-induced activation of p53 is an essential cellular response to prevent aberrant cell proliferation and cancer development. The ubiquitin ligase MDM2 promotes p53 degradation and limits the duration of p53 activation. It remains unclear, however, how p53 persistently escapes MDM2-mediated negative control for making appropriate cell fate decisions. Here we report that TBP-like protein (TLP), a member of the TBP family, is a new regulatory factor for the p53-MDM2 interplay and thus for p53 activation. We found that TLP acts to stabilize p53 protein to ensure long-lasting p53 activation, leading to potentiation of p53-induced apoptosis and senescence after genotoxic stress. Mechanistically, TLP interferes with MDM2 binding and ubiquitination of p53. Moreover, single cell imaging analysis shows that TLP depletion accelerates MDM2-mediated nuclear export of p53. We further show that a cervical cancer-derived TLP mutant has less p53 binding ability and lacks a proliferation-repressive function. Our findings uncover a role of TLP as a competitive MDM2 blocker, proposing a novel mechanism by which p53 escapes the p53-MDM2 negative feedback loop to modulate cell fate decisions.
authors.affiliation: Department of Biology, Graduate School of Science, Chiba University, Chiba 263-8522, Japan. Electronic address: rmaeda@chiba-u.jp.
authors.forename: Ryo
authors.initials: R
authors.lastname: Maeda
authors.affiliation: Department of Biology, Graduate School of Science, Chiba University, Chiba 263-8522, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tamashiro
authors.affiliation: Department of Biology, Graduate School of Science, Chiba University, Chiba 263-8522, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Takano
authors.affiliation: Graduate School of Horticulture, Chiba University, Chiba 271-8510, Japan.
authors.forename: Hiro
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Biology, Graduate School of Science, Chiba University, Chiba 263-8522, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Graduate School of Nanobioscience, Yokohama City University, Yokohama 236-0027, Japan.
authors.forename: Shinta
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Biology, Graduate School of Science, Chiba University, Chiba 263-8522, Japan.
authors.forename: Waka
authors.initials: W
authors.lastname: Kojima
authors.affiliation: Graduate School of Nanobioscience, Yokohama City University, Yokohama 236-0027, Japan; Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Adachi
authors.affiliation: Department of Biology, Graduate School of Science, Chiba University, Chiba 263-8522, Japan.
authors.forename: Kiyoe
authors.initials: K
authors.lastname: Ura
authors.affiliation: Department of Biology, Graduate School of Science, Chiba University, Chiba 263-8522, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Endo
authors.affiliation: Department of Biology, Graduate School of Science, Chiba University, Chiba 263-8522, Japan.
authors.forename: Taka-Aki
authors.initials: TA
authors.lastname: Tamura
mesh_terms: D017209:Apoptosis; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D060066:Protein Interaction Maps; D055550:Protein Stability; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000032:analysis / Q000378:metabolism*; D035182:TATA Box Binding Protein-Like Proteins / Q000032:analysis / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D035182:TATA Box Binding Protein-Like Proteins; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
keywords: cancer; cell growth; p53; protein stability; transcription factor