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TBP-like Protein (TLP) Disrupts the p53-MDM2 Interaction and Induces Long-lasting p53 Activation*

Open AccessPublished:January 12, 2017DOI:https://doi.org/10.1074/jbc.M116.763318
      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.

      Introduction

      The tumor suppressor p53 is a potent transcription factor that promotes cell cycle arrest, senescence, and apoptosis in response to various types of stress (
      • Vogelstein B.
      • Lane D.
      • Levine A.J.
      Surfing the p53 network.
      ). Although p53 orchestrates more than 100 target genes, it is usually retained in an “off” state because of its rapid turnover (
      • Wei C.L.
      • Wu Q.
      • Vega V.B.
      • Chiu K.P.
      • Ng P.
      • Zhang T.
      • Shahab A.
      • Yong H.C.
      • Fu Y.
      • Weng Z.
      • Liu J.
      • Zhao X.D.
      • Chew J.L.
      • Lee Y.L.
      • Kuznetsov V.A.
      • et al.
      A global map of p53 transcription-factor binding sites in the human genome.
      ). This negative regulation is achieved mainly through recruitment of MDM2 to the transactivation domain (TAD)
      The abbreviations used are: TAD
      transactivation domain
      CBP
      CREB (cAMP-response element-binding protein)-binding protein
      TAF1
      TBP-associated factor 1
      TLP
      TBP-like protein
      CHX
      cycloheximide
      FH
      FLAG-His
      Dox
      doxycycline
      PI
      protease inhibitor
      qPCR
      quantitative PCR
      NEM
      N-ethylmaleimide.
      in the N terminus of p53 and the E3 ubiquitin ligase activity of MDM2 (
      • Kussie P.H.
      • Gorina S.
      • Marechal V.
      • Elenbaas B.
      • Moreau J.
      • Levine A.J.
      • Pavletich N.P.
      Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain.
      ,
      • Haupt Y.
      • Maya R.
      • Kazaz A.
      • Oren M.
      Mdm2 promotes the rapid degradation of p53.
      • Kubbutat M.H.
      • Jones S.N.
      • Vousden K.H.
      Regulation of p53 stability by Mdm2.
      ). MDM2 mediates both the monoubiquitination and polyubiquitination of p53 and promotes its degradation (
      • Li M.
      • Brooks C.L.
      • Wu-Baer F.
      • Chen D.
      • Baer R.
      • Gu W.
      Mono- versus polyubiquitination: differential control of p53 fate by Mdm2.
      ). Monoubiquitination at the DNA binding domain and the C-terminal domain of p53 acts as not only a scaffold of polyubiquitination but also a signal for p53 nuclear export (
      • Geyer R.K.
      • Yu Z.K.
      • Maki C.G.
      The MDM2 RING-finger domain is required to promote p53 nuclear export.
      ,
      • Nie L.
      • Sasaki M.
      • Maki C.G.
      Regulation of p53 nuclear export through sequential changes in conformation and ubiquitination.
      • Carter S.
      • Bischof O.
      • Dejean A.
      • Vousden K.H.
      C-terminal modifications regulate MDM2 dissociation and nuclear export of p53.
      ). In the cytoplasm, other E3 ligases and E4 enzymes such as CBP/p300 can lead polyubiquitination of p53 and 26S proteasomal degradation (
      • Shi D.
      • Pop M.S.
      • Kulikov R.
      • Love I.M.
      • Kung A.L.
      • Kung A.
      • Grossman S.R.
      CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53.
      ). Additionally, given that p53 principally works as a transcriptional factor in the nucleus, the nuclear export of p53 is a major step that limits p53 function.
      The p53-MDM2 interplay forms the basis of p53 dynamics, and several transcription-related factors regulate p53 activity (
      • Beckerman R.
      • Prives C.
      Transcriptional regulation by p53.
      ). Upon genotoxic stresses, p53 is phosphorylated at Thr-18 and Ser-20, both of which are critical for MDM2 binding, leading to the dissociation of the p53-MDM2 interaction (
      • Unger T.
      • Juven-Gershon T.
      • Moallem E.
      • Berger M.
      • Vogt Sionov R.
      • Lozano G.
      • Oren M.
      • Haupt Y.
      Critical role for Ser-20 of human p53 in the negative regulation of p53 by Mdm2.
      ,
      • Sakaguchi K.
      • Saito S.
      • Higashimoto Y.
      • Roy S.
      • Anderson C.W.
      • Appella E.
      Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase: effect on MDM2 binding.
      ). p300/CBP then binds to the p53 TAD and acetylates multiple lysine residues in the C-terminal domain of p53 (
      • Teufel D.P.
      • Bycroft M.
      • Fersht A.R.
      Regulation by phosphorylation of the relative affinities of the N-terminal transactivation domains of p53 for p300 domains and Mdm2.
      ), and p53 escapes from degradation and becomes active as a transcription factor (
      • Tang Y.
      • Zhao W.
      • Chen Y.
      • Zhao Y.
      • Gu W.
      Acetylation is indispensable for p53 activation.
      ). Activated p53 in turn induces the expression of MDM2. High levels of MDM2 associate with HDAC1 and deacetylate p53 to promote its degradation (
      • Ito A.
      • Kawaguchi Y.
      • Lai C.H.
      • Kovacs J.J.
      • Higashimoto Y.
      • Appella E.
      • Yao T.P.
      MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation.
      ). In the late phase of the stress response, TBP-associated factor 1 (TAF1), the largest subunit of the basal transcription factor TFIID, phosphorylates p53 at Thr-55 and dissociates p53 from the p21 promoter by elevating MDM2 binding affinity of p53 (
      • Li H.H.
      • Li A.G.
      • Sheppard H.M.
      • Liu X.
      Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: a role for TAF1 in cell G1 progression.
      ,
      • Wu Y.
      • Lin J.C.
      • Piluso L.G.
      • Dhahbi J.M.
      • Bobadilla S.
      • Spindler S.R.
      • Liu X.
      Phosphorylation of p53 by TAF1 inactivates p53-dependent transcription in the DNA damage response.
      ). In addition, some unknown transcription-related factors may also be involved in p53 regulation, and identification of a novel regulator of the p53-MDM2 interplay is critical for understanding the mechanisms underlying p53 dynamics.
      TLP is a member of the TBP family and is also named TBP-related factor 2 (TRF2) and TBP-like 1 (TBPL1) (
      • Ohbayashi T.
      • Makino Y.
      • Tamura T.
      Identification of a mouse TBP-like protein (TLP) distantly related to the Drosophila TBP-related factor.
      ,
      • Rabenstein M.D.
      • Zhou S.
      • Lis J.T.
      • Tjian R.
      TATA box-binding protein (TBP)-related factor 2 (TRF2), a third member of the TBP family.
      ). TLP has 38% identity to the C-terminal conserved region of TBP and mimics the function of a basal transcription factor in the regulation of various biological processes (
      • Zehavi Y.
      • Kedmi A.
      • Ideses D.
      • Juven-Gershon T.
      TRF2: TRansForming the view of general transcription factors.
      ). TLP, but not TBP, is associated with a number of TATA-less promoters and mediates RNA polymerase II-driven transcription from those promoters including ribosomal protein genes (
      • Wang Y.L.
      • Duttke S.H.
      • Chen K.
      • Johnston J.
      • Kassavetis G.A.
      • Zeitlinger J.
      • Kadonaga J.T.
      TRF2, but not TBP, mediates the transcription of ribosomal protein genes.
      ). Upon genotoxic stress, TLP represses cell growth via regulation of cell cycle-associated genes such as wee1, Cdkn1a (p21), and Trp63 (
      • Tanaka Y.
      • Nanba Y.A.
      • Park K.A.
      • Mabuchi T.
      • Suenaga Y.
      • Shiraishi S.
      • Shimada M.
      • Nakadai T.
      • Tamura T.
      Transcriptional repression of the mouse wee1 gene by TBP-related factor 2.
      ,
      • Suenaga Y.
      • Ozaki T.
      • Tanaka Y.
      • Bu Y.
      • Kamijo T.
      • Tokuhisa T.
      • Nakagawara A.
      • Tamura T.
      TATA-binding protein (TBP)-like protein is engaged in etoposide-induced apoptosis through transcriptional activation of human TAp63 gene.
      ). We have also found that TLP binds to the TAD of p53, as does TBP, and enhances p21 expression in a p53-dependent manner (
      • Horikoshi N.
      • Usheva A.
      • Chen J.
      • Levine A.J.
      • Weinmann R.
      • Shenk T.
      Two domains of p53 interact with the TATA-binding protein, and the adenovirus 13S E1A protein disrupts the association, relieving p53-mediated transcriptional repression.
      ,
      • Suzuki H.
      • Ito R.
      • Ikeda K.
      • Tamura T.
      TATA-binding Protein (TBP)-like protein is required for p53-dependent transcriptional activation of upstream promoter of p21Waf1/Cip1 gene.
      • Maeda R.
      • Suzuki H.
      • Tanaka Y.
      • Tamura T.
      Interaction between transactivation domain of p53 and middle part of TBP-like protein (TLP) is involved in TLP-stimulated and p53-activated transcription from the p21 upstream promoter.
      ). However, little is known about the most fundamental question of how TLP regulates p53 target genes or p53 itself.
      Here we aimed to investigate the role of TLP in p53 regulation and present evidence that TLP is a new regulatory factor of the p53-MDM2 interplay. In the genotoxic stress response, TLP promotes p53-driven apoptosis and senescence by mediating persistent p53 activation. TLP binds to the p53 TAD and inhibits MDM2 recruitment to p53, which results in suppression of p53 ubiquitination. We also aimed to real time chasing of p53 nuclear export and show that TLP is essential for suppressing MDM2-driven nuclear export of p53. Moreover, a cervical cancer-derived TLP mutant has little p53 binding ability and does not suppress cell growth. Taken together, our findings indicate that TLP disrupts the p53-MDM2 interaction and mediates long-lasting p53 activation in response to genotoxic stress.

      Discussion

      Recent studies have proposed that the concentration and duration of activated p53 and its target genes determine the cell fate decision such as cell cycle arrest, apoptosis, and senescence (
      • Leontieva O.V.
      • Gudkov A.V.
      • Blagosklonny M.V.
      Weak p53 permits senescence during cell cycle arrest.
      ,
      • Kracikova M.
      • Akiri G.
      • George A.
      • Sachidanandam R.
      • Aaronson S.A.
      A threshold mechanism mediates p53 cell fate decision between growth arrest and apoptosis.
      ). In the present study we showed that TLP stabilizes the p53 protein, thereby enhancing its function. We demonstrated that the TLP function is evident in the late phase of a high dose of UV exposure and is important to mediate the induction of apoptosis and senescence. This indicates that TLP is required for persistent p53 activation and direction of the cell fate decision. We further showed that TLP disrupts the p53-MDM2 interaction and demonstrated that TLP prevented p53 degradation by interfering with MDM2-mediated ubiquitination and nuclear export of p53. Moreover, we found that the expression of TLP is increased at the protein level in the late phase of UV irradiation, suggesting that elevated TLP binds to p53 and releases p53 from the MDM2-mediated negative control. In contrast, the MDM2 function toward p53 becomes stronger when the levels of TLP in cells are low. Notably, MDM2 is one of the targets of p53 and thus is down-regulated by TLP knockdown. Although this result seems to cause p53 stabilization, TLP depletion decreased p53 levels. This situation is because the turnover of p53 became faster in TLP-depleted cells. These phenomena suggest that TLP maintains the protein levels of p53 and MDM2 in cells. Our findings indicate that TLP acts as an MDM2 blocker in the p53-MDM2 negative feedback loop and establishes a novel mechanism for long-lasting p53 activation to direct appropriate cell fate decision (Fig. 7).
      Figure thumbnail gr7
      FIGURE 7Model of the action of TLP on p53-MDM2 interplay. A, regulation of the p53-MDM2 negative feedback loop by TLP. TLP interrupts MDM2-mediated negative regulation toward p53. B, TLP promotes p53 function by disrupting p53 binding of MDM2. TLP binding to p53 interferes with the p53-MDM2 interaction and retains p53 in the nucleus. As a consequence, TLP promotes p53 functions such as growth inhibition and senescence induction.
      TBP recognizes the TATA element in promoters of many RNA polymerase II-driven genes, enabling it to constitute the basic transcriptional machinery on those promoters (
      • Hernandez N.
      TBP, a universal eukaryotic transcription factor?.
      ). TLP has been identified as a TBP family protein and is considered to be involved in various biological processes (
      • Zehavi Y.
      • Kedmi A.
      • Ideses D.
      • Juven-Gershon T.
      TRF2: TRansForming the view of general transcription factors.
      ,
      • Wang Y.L.
      • Duttke S.H.
      • Chen K.
      • Johnston J.
      • Kassavetis G.A.
      • Zeitlinger J.
      • Kadonaga J.T.
      TRF2, but not TBP, mediates the transcription of ribosomal protein genes.
      ). TLP binds to some general transcription factors, such as TFIIA, and interferes with the TBP-TFIIA interaction. The TLP-bound TFIIA precursor is protected from Taspase1-mediated cleavage, which leads to inhibition of TBP-mediated transcription (
      • Suzuki H.
      • Isogai M.
      • Maeda R.
      • Ura K.
      • Tamura T.
      TBP-like protein (TLP) interferes with Taspase1-mediated processing of TFIIA and represses TATA box gene expression.
      ). Perhaps one role of TLP may be as a blocker of protein-protein interactions. We note that TLP depletion in HeLa cells increased p53 mRNA levels, although p53 protein levels were down-regulated in such a condition. This phenomenon seems to be governed by p53-independent TLP function, suggesting that TLP has multiple roles in both p53-dependent and -independent manners.
      The interplay between p53 and transcription-related factors in stress response is highly complicated. It is basically unknown whether basal transcription factors exert their positive or negative effects on p53 function. TFIIH, a multiprotein complex involved in both transcription and DNA repair, and TBP, both, activate p53-driven transcription (
      • Chen X.
      • Farmer G.
      • Zhu H.
      • Prywes R.
      • Prives C.
      Cooperative DNA binding of p53 with TFIID (TBP): a possible mechanism for transcriptional activation.
      ,
      • Xiao H.
      • Pearson A.
      • Coulombe B.
      • Truant R.
      • Zhang S.
      • Regier J.L.
      • Triezenberg S.J.
      • Reinberg D.
      • Flores O.
      • Ingles C.J.
      Binding of basal transcription factor TFIIH to the acidic activation domains of VP16 and p53.
      ). In contrast, TAF1 phosphorylates p53 at Thr-55 and mediates degradation of p53 (
      • Li H.H.
      • Li A.G.
      • Sheppard H.M.
      • Liu X.
      Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: a role for TAF1 in cell G1 progression.
      ,
      • Wu Y.
      • Lin J.C.
      • Piluso L.G.
      • Dhahbi J.M.
      • Bobadilla S.
      • Spindler S.R.
      • Liu X.
      Phosphorylation of p53 by TAF1 inactivates p53-dependent transcription in the DNA damage response.
      ). TAF1-mediated phosphorylation of p53 increases p53-MDM2 interaction and releases p53 from the p21 promoter in the late phase of UV irradiation. In this study we confirmed that p53 is actually recruited to the promoters of its target genes. However, TLP is not significantly recruited to promoters of representative p53 target genes. These results suggest that TLP affects p53 activity through a mechanism distinct from association of transcription machineries on a promoter. Hence, our findings may help to resolve the mechanisms underlying p53 dynamics and linking basal transcription factors to p53 activation.
      The nuclear export of p53 has also been widely discussed because a number of cancers show cytoplasmic localization of p53 (
      • Moll U.M.
      • Riou G.
      • Levine A.J.
      Two distinct mechanisms alter p53 in breast cancer: mutation and nuclear exclusion.
      ,
      • Goldman S.C.
      • Chen C.Y.
      • Lansing T.J.
      • Gilmer T.M.
      • Kastan M.B.
      The p53 signal transduction pathway is intact in human neuroblastoma despite cytoplasmic localization.
      ). It has been speculated that MDM2 induces a conformational change of p53 to expose the nuclear export signal at the C-terminal domain of p53. MDM2 then mediates p53 monoubiquitination and promotes its nuclear export (
      • Li M.
      • Brooks C.L.
      • Wu-Baer F.
      • Chen D.
      • Baer R.
      • Gu W.
      Mono- versus polyubiquitination: differential control of p53 fate by Mdm2.
      ,
      • Geyer R.K.
      • Yu Z.K.
      • Maki C.G.
      The MDM2 RING-finger domain is required to promote p53 nuclear export.
      • Nie L.
      • Sasaki M.
      • Maki C.G.
      Regulation of p53 nuclear export through sequential changes in conformation and ubiquitination.
      ). We established a method for chasing real-time nuclear export of p53 using Dronpa and showed that TLP depletion increases the nuclear export of p53. However, TLP depletion does not fully export p53 to the cytoplasm, and the remaining p53 still activates transcription. These results suggest that TLP depletion is not sufficient for abolishing p53 activity. Because many factors cooperatively and rapidly regulate the p53 level in normal cells (
      • Carter S.
      • Bischof O.
      • Dejean A.
      • Vousden K.H.
      C-terminal modifications regulate MDM2 dissociation and nuclear export of p53.
      ), and real-time analysis using Dronpa may help to clarify such a complicated process.
      About half of all human cancers have mutations in the p53 gene, whereas the reason why some cancer cells still retain wild-type p53 has not been fully elucidated (
      • Freed-Pastor W.A.
      • Prives C.
      Mutant p53: one name, many proteins.
      ). In these cancer cells several altered cellular processes are likely to suppress p53 function. In this study we used HCT116 and HeLa cells. Interestingly, TLP-elevated p53 stability was clearly observed in HeLa cells. Human papillomavirus E6 protein in HeLa cell leads p53 to degradation (
      • Freedman D.A.
      • Levine A.J.
      Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6.
      ), and because of these vulnerable conditions, TLP function for p53 may be strengthened. Furthermore, we found that multiple TLP mutations in human cancers were mapped in the p53 binding region of TLP. We used a TLP mutant, D99H, which is found in wild-type p53-expressing cervical cancer. This mutant had a weak p53 binding ability and exhibited a defect in suppression of cell growth. These findings are consistent with the notion that wild-type p53-expressing cancer cells have some p53-suppressive factors. Consequently, TLP is a novel regulator of the p53-MDM2 interplay that provides cells with sensitivity to genotoxic stress by mediating long-lasting p53 activation.

      Author Contributions

      R. M., N. A., K. U., T. E., and T. T. conceived and designed the experiments. R. M., H. Tamashiro, K. T., H. S., S. S., and W. K. performed the experiments. R. M. and H. Takahashi analyzed the data. R. M., H. S., and T. T. contributed reagents, materials, and analysis tools. R. M. and T. T. wrote the paper.

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