The Conserved CPH Domains of Cul7 and PARC Are Protein-Protein Interaction Modules That Bind the Tetramerization Domain of p53

Cul7 is a member of the Cullin Ring Ligase (CRL) family and is required for normal mouse development and cellular proliferation. Recently, a region of Cul7 that is highly conserved in the p53-associated, Parkin-like cytoplasmic protein PARC, was shown to bind p53 directly. Here we identify the CPH domains (conserved domain within Cul7, PARC, and HERC2 proteins) of both Cul7 and PARC as p53 interaction domains using size exclusion chromatography and NMR spectroscopy. We present the first structure of the evolutionarily conserved CPH domain and provide novel insight into the Cul7-p53 interaction. The NMR structure of the Cul7-CPH domain reveals a fold similar to peptide interaction modules such as the SH3, Tudor, and KOW domains. The p53 interaction surface of both Cul7 and PARC CPH domains was mapped to a conserved surface distinct from the analogous peptide-binding regions of SH3, KOW, and Tudor domains, suggesting a novel mode of interaction. The CPH domain interaction surface of p53 resides in the tetramerization domain and is formed by residues contributed by at least two subunits. Cul7 is a member of the Cullin Ring Ligase (CRL) family and is required for normal mouse development and cellular proliferation. Recently, a region of Cul7 that is highly conserved in the p53-associated, Parkin-like cytoplasmic protein PARC, was shown to bind p53 directly. Here we identify the CPH domains (conserved domain within Cul7, PARC, and HERC2 proteins) of both Cul7 and PARC as p53 interaction domains using size exclusion chromatography and NMR spectroscopy. We present the first structure of the evolutionarily conserved CPH domain and provide novel insight into the Cul7-p53 interaction. The NMR structure of the Cul7-CPH domain reveals a fold similar to peptide interaction modules such as the SH3, Tudor, and KOW domains. The p53 interaction surface of both Cul7 and PARC CPH domains was mapped to a conserved surface distinct from the analogous peptide-binding regions of SH3, KOW, and Tudor domains, suggesting a novel mode of interaction. The CPH domain interaction surface of p53 resides in the tetramerization domain and is formed by residues contributed by at least two subunits. The ubiquitin-proteosome system plays an important role in controlling diverse biological processes, ranging from signal transduction to cell cycle control (1Hochstrasser M. Curr. Opin. Cell Biol. 1995; 7: 215-223Crossref PubMed Scopus (775) Google Scholar, 2Cardozo T. Pagano M. Nat. Rev. Mol. Cell Biol. 2004; 5: 739-751Crossref PubMed Scopus (860) Google Scholar). These complex processes are controlled via specific degradation of individual or groups of proteins. Protein degradation via the ubiquitin path-way involves two successive steps: tagging of the substrate by covalent attachment of multiple ubiquitin molecules (ubiquitylation) and degradation of the tagged protein by 26 S proteo-some complex with release of free and reusable ubiquitin (3Schwartz A.L. Ciechanover A. Annu. Rev. Med. 1999; 50: 57-74Crossref PubMed Scopus (372) Google Scholar). Ubiquitylation is the ultimate result of coordinated activity of an enzymatic cascade, which includes a ubiquitin-activating enzyme (E1), 3The abbreviations used are: E1, ubiquitin-activating enzyme; E2, ubiquitin carrier protein; E3, ubiquitin-ligating enzyme; TD, tetramerization domain; TCEP, Tris(2-carboxyethyl) phosphine hydrochloride; NOE, nuclear Over-hauser effect; NOESY, NOE spectroscopy; MQLR, M340Q/L344R; HSQC, heteronuclear correlated spectroscopy; TOCSY, total correlated spectroscopy. 3The abbreviations used are: E1, ubiquitin-activating enzyme; E2, ubiquitin carrier protein; E3, ubiquitin-ligating enzyme; TD, tetramerization domain; TCEP, Tris(2-carboxyethyl) phosphine hydrochloride; NOE, nuclear Over-hauser effect; NOESY, NOE spectroscopy; MQLR, M340Q/L344R; HSQC, heteronuclear correlated spectroscopy; TOCSY, total correlated spectroscopy. a ubiquitin-conjugating enzyme (E2), and ubiquitin-ligating (E3) enzymes. The E3 ligases are the “brain” of this process and determine substrate specificity (4Petroski M.D. Deshaies R.J. Nat. Rev. Mol. Cell Biol. 2005; 6: 9-20Crossref PubMed Scopus (1635) Google Scholar, 5Joazeiro C.A. Weissman A.M. Cell. 2000; 102: 549-552Abstract Full Text Full Text PDF PubMed Scopus (1025) Google Scholar). Cul7, is a recently identified member of the Cullin family of ubiquitin E3 ligases, localizes predominantly in the cytoplasm (6Andrews P. He Y.J. Xiong Y. Oncogene. 2006; 25: 4534-4548Crossref PubMed Scopus (79) Google Scholar), and forms a unique Skp1-Cul7-Fbx29-like complex with FBXW8, a WD40 containing F-box protein (7Dias D.C. Dolios G. Wang R. Pan Z.Q. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16601-16606Crossref PubMed Scopus (137) Google Scholar, 8Arai T. Kasper J.S. Skaar J.R. Ali S.H. Takahashi C. DeCaprio J.A. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 9855-9860Crossref PubMed Scopus (117) Google Scholar, 9Tsunematsu R. Nishiyama M. Kotoshiba S. Saiga T. Kamura T. Nakayama K.I. Mol. Cell Biol. 2006; 26: 6157-6169Crossref PubMed Scopus (47) Google Scholar). Although a target substrate for FBXW8 has not been yet identified, Cul7 recruits RBX1 to form a Skp1-Cul7-Fbx29-like E3 ubiquitin ligase complex (7Dias D.C. Dolios G. Wang R. Pan Z.Q. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16601-16606Crossref PubMed Scopus (137) Google Scholar, 8Arai T. Kasper J.S. Skaar J.R. Ali S.H. Takahashi C. DeCaprio J.A. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 9855-9860Crossref PubMed Scopus (117) Google Scholar). The biological function of Cul7 is unclear. However, Cul7 appears to play an important role in development (8Arai T. Kasper J.S. Skaar J.R. Ali S.H. Takahashi C. DeCaprio J.A. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 9855-9860Crossref PubMed Scopus (117) Google Scholar, 9Tsunematsu R. Nishiyama M. Kotoshiba S. Saiga T. Kamura T. Nakayama K.I. Mol. Cell Biol. 2006; 26: 6157-6169Crossref PubMed Scopus (47) Google Scholar), and overexpression of Cul7 accelerates the rate of cell proliferation (6Andrews P. He Y.J. Xiong Y. Oncogene. 2006; 25: 4534-4548Crossref PubMed Scopus (79) Google Scholar). Cul7 has significant sequence similarity (see Fig. 1) with the p53-associated, Parkin-like cytoplasmic protein, PARC (10Nikolaev A.Y. Li M. Puskas N. Qin J. Gu W. Cell. 2003; 112: 29-40Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar). Both proteins contain CPH (domain that is conserved in Cul7, PARC, and HERC2 proteins) (11Kasper J.S. Arai T. Decaprio J.A. Biochem. Biophys. Res. Commun. 2006; 348: 132-138Crossref PubMed Scopus (24) Google Scholar), DOC (DOC1/APC10), and Cullin homology domains (see Fig. 1A) that are linked with E3 ligase function, suggesting that PARC and Cul7 may both function as E3 ubiquitin ligases. PARC has been shown to sequester p53 in the cytoplasm via interaction between the N terminus of PARC and the C terminus of p53 (10Nikolaev A.Y. Li M. Puskas N. Qin J. Gu W. Cell. 2003; 112: 29-40Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar). Cul7 may perform functions similar to those of PARC given their degree of sequence similarity and have also recently been shown to interact directly with p53 via its N terminus (6Andrews P. He Y.J. Xiong Y. Oncogene. 2006; 25: 4534-4548Crossref PubMed Scopus (79) Google Scholar, 11Kasper J.S. Arai T. Decaprio J.A. Biochem. Biophys. Res. Commun. 2006; 348: 132-138Crossref PubMed Scopus (24) Google Scholar). Recently published data identified a domain within Cul7 that is necessary and sufficient for p53 binding (6Andrews P. He Y.J. Xiong Y. Oncogene. 2006; 25: 4534-4548Crossref PubMed Scopus (79) Google Scholar, 11Kasper J.S. Arai T. Decaprio J.A. Biochem. Biophys. Res. Commun. 2006; 348: 132-138Crossref PubMed Scopus (24) Google Scholar). This domain (the CPH domain) also contributes to the cytoplasmic localization of Cul7 (6Andrews P. He Y.J. Xiong Y. Oncogene. 2006; 25: 4534-4548Crossref PubMed Scopus (79) Google Scholar, 11Kasper J.S. Arai T. Decaprio J.A. Biochem. Biophys. Res. Commun. 2006; 348: 132-138Crossref PubMed Scopus (24) Google Scholar). This, taken together with its similarity to PARC, another p53 interacting protein and putative E3 ligase, argues for more detailed investigation of these two proteins with respect to their interactions with p53. Understanding the structure, function, and interactions of Cul7/PARC domains with p53 will help to elucidate their involvement in ubiquitylation pathways and the circumstances through which they impinge on the p53 pathway. Inactivation of p53 is considered an important step in the development of many human cancers. It is therefore important to determine how p53 levels are regulated and how this regulation is altered in cancer. Transcriptionally active p53 protein is tetrameric, and in this conformation it binds with high affinity to DNA or interacts more efficiently with various other proteins (12Hainaut P. Hollstein M. Adv. Cancer Res. 2000; 77: 81-137Crossref PubMed Scopus (833) Google Scholar, 13Ko L.J. Prives C. Genes Dev. 1996; 10: 1054-1072Crossref PubMed Scopus (2279) Google Scholar). The tetramerization domain is therefore important for p53 function because it ensures that the protein is endowed with its correct conformation. The oligomerization state of p53 is also thought to contribute to its subcellular localization by virtue of a cryptic nuclear export sequence that is only exposed in nontetrameric forms of the protein (14Stommel J.M. Marchenko N.D. Jimenez G.S. Moll U.M. Hope T.J. Wahl G.M. EMBO J. 1999; 18: 1660-1672Crossref PubMed Scopus (597) Google Scholar). Here we show that the conserved CPH domain of Cul7 interacts with the tetramerization domain (TD) of p53. To gain insight into Cul7 and its interaction with p53, we have solved the three-dimensional structure of the CPH domain of human Cul7 by NMR spectroscopy. The structure reveals a small domain with a fold similar to SH3, KOW, and Tudor domains, suggesting that it may function as a peptide-binding module. Chemical shift perturbation studies map the p53-TD interaction to regions distinct from the analogous peptide-binding surface of Tudor, KOW, and SH3 domains. Our NMR data also suggest that the Cul7-p53 interaction depends on the p53 oligomerization status. The structures and interactions were compared with the homologous region of PARC, confirming a similar interaction with the CPH domain of PARC. Cloning, Expression, and Purification—The coding regions for Cul7 360-460 and PARC 366-465 (CPH-containing domains) and the p53 TD (residues 310-360) were PCR-amplified from human Cul7 cDNA and human p53 cDNA, respectively, and subcloned into the pET15b expression vector (Novagen) at the 5′-NdeI site and 3′-BamHI site. The p53 fragment was expressed in Escherichia coli BL21 (DE3)-pLysS cells (Stratagene), whereas Cul7 and PARC constructs were expressed in E. coli BL21 (DE3) Rosetta cells (Novagen). For large scale production, the cells were grown at 37 °C until A600 nm of ∼1.0, and then the cultures were induced with 1 mm isopropyl-β-d-thiogalactopyranoside for 5 h at room temperature before harvesting. The bacteria were grown in LB medium for nonlabeled proteins and in M9-defined medium supplemented with [15N]ammonium chloride (0.8 g/liter) and d-glucose. For the 15N/13C-labeled samples, d-glucose was replaced by 13C6-d-glucose (4 g/liter). These highly expressed proteins were purified by Talon (BD) affinity chromatography under native conditions and eluted with buffer containing 500 mm imidazole. The proteins were treated with thrombin and further purified by size exclusion chromatography using a HiLoad 26/60 Super-dex-75 column (GE Healthcare). Gel Filtration Studies—A calibrated Superdex 75 column was equilibrated with 25 mm Tris, pH mm mm mm TCEP, mm Cul7-CPH and p53-TD were in and and to chromatography (see Fig. shown in and were and on NMR of the were at 25 °C on and 500 with and of the NMR were at pH with 25 mm Tris, mm mm mm mm The NMR with a protein ranging between and were on or and domains and The were with S. G. J. A. J. 1995; 6: PubMed Scopus Google and with the and G. of in the and was used to the The of of and of Cul7-CPH domain was with the A. C.A. A. C. M. 2005; PubMed Scopus Google with using data from and The of of and of the domain were on the and The of and domains the of p53-TD were in to the proteins. for structure were from and were with the The were into and to and The for and were from of using G. A. J. 1999; PubMed Scopus Google Scholar). were were using G.M. P. J.S. J. M. R.J. T. Biol. PubMed Scopus Google with its of structure and NOE were NOE was using the A. M. J. 2004; PubMed Scopus (24) Google Scholar). were in structure on using N. A.M. G.M. A. Nat. Biol. PubMed Scopus Google with of the of structures were for 1) NOE by a for and the of the and of the using the M. A. J. PubMed Scopus Google Scholar). The structures were using by a in C.A. A.M. M. 2003; 50: PubMed Scopus Google Scholar). The structures were using R. M. J. Mol. 1996; Scopus Google Scholar), J.A. R. J.M. J. 1996; PubMed Scopus Google Scholar), and A. R. 2006; Scopus Google Scholar). homology of was from the NMR structure of the Cul7-CPH using NMR of p53-TD and Cul7-CPH proteins were into the Cul7-CPH and p53-TD in of and respectively, until further in were in the were and of domain was with The of the form of and domains the of p53-TD were a in compared with the were those N. A.M. G.M. A. Nat. Biol. PubMed Scopus Google Scholar). The shift were using the that Cul7 and PARC have high sequence in their domains and both interact with p53 via their domains, we to identify a domain to both proteins that interact with p53. for domain constructs of Cul7, a fragment (residues was identified from not a CPH a homologous sequence within the Cul7, PARC, and HERC2 proteins (11Kasper J.S. Arai T. Decaprio J.A. Biochem. Biophys. Res. Commun. 2006; 348: 132-138Crossref PubMed Scopus (24) Google Scholar, U. J. R. 2005; PubMed Scopus Google of the Cul7-CPH structure of the Cul7-CPH was by heteronuclear NMR spectroscopy. The protein used for the studies residues 360-460 of human However, only residues a The residues are as by and small heteronuclear NOE not The protein is in as by size exclusion chromatography (see Fig. The structure was using and from three-dimensional and NOE and from and of the NOE of the structure of structures of from NMR for from covalent from were for residues is using the of structures of of structures of The were for residues is using the (1Hochstrasser M. Curr. Opin. Cell Biol. 1995; 7: 215-223Crossref PubMed Scopus (775) Google Scholar). in a The CPH CPH domain has a of and an are by a and are by a whereas and are linked by a The structure an residues and are exposed and form a that may in interactions residues and form an for interaction. for similar proteins a of proteins with of The KOW domain and the SH3 domain of the Protein are the two and they significant sequence The are SH3 the Tudor domains of and are in the and and This that the CPH domain may a interaction a protein, because the KOW domain of T. S. R. Wahl EMBO J. 2002; PubMed Scopus Google and the Tudor domain of G. J. E. R. S. 2004; Full Text Full Text PDF PubMed Scopus Google have been in both these The of in the CPH domain is to that in SH3, Tudor, and KOW domains with on the of is significant in the and of the that contribute to peptide binding in For the of SH3 domain PubMed Scopus Google of whereas are only residues in the of the Cul7-CPH the similar domains in the of binding binding by SH3 domains is by a surface that is in residues and by various residues in the and Protein Sci. 2000; PubMed Scopus Google Scholar). The Tudor domain of 1 and to bind to of P. R. G. U. M. Nat. Biol. PubMed Scopus Google Scholar). The KOW domain bind proteins and at the via T. S. R. Wahl EMBO J. 2002; PubMed Scopus Google Scholar). the fold in a unique to interact with it to a surface for Cul7 from domain The CPH with region of Cul7 has been by and to a p53 binding (6Andrews P. He Y.J. Xiong Y. Oncogene. 2006; 25: 4534-4548Crossref PubMed Scopus (79) Google Scholar, 11Kasper J.S. Arai T. Decaprio J.A. Biochem. Biophys. Res. Commun. 2006; 348: 132-138Crossref PubMed Scopus (24) Google Scholar). Recently Kasper (11Kasper J.S. Arai T. Decaprio J.A. Biochem. Biophys. Res. Commun. 2006; 348: 132-138Crossref PubMed Scopus (24) Google that residues of Cul7 were sufficient for with p53. of Cul7 were shown to with p53 (6Andrews P. He Y.J. Xiong Y. Oncogene. 2006; 25: 4534-4548Crossref PubMed Scopus (79) Google Scholar, 11Kasper J.S. Arai T. Decaprio J.A. Biochem. Biophys. Res. Commun. 2006; 348: 132-138Crossref PubMed Scopus (24) Google Scholar). both of these the CPH we further the was for the p53 interaction using size exclusion chromatography and NMR shown in Fig. Cul7-CPH is with an of p53-TD at high protein Cul7-CPH with p53-TD as a complex in NMR in which the was with p53-TD shift for residues The free and forms of the protein are in on the NMR suggesting that the affinity between CPH and p53-TD is in the of the complex was by least of the shift binding as a function of the total as J. Mol. Biol. 2003; PubMed Scopus Google Scholar). shift of and the of a of was This result is in with the the of two proteins only Cul7-CPH is by p53-TD and proteins are at high and mm for Cul7-CPH and interaction was proteins were at shown in The p53-TD peptide-binding region as those residues with shift includes and and forms a surface on the protein the for and that of was residues this surface and also shift and Fig. These residues form a between and an for interaction with p53 these residues also the conserved residues and suggesting that p53 binds to Cul7-CPH through a conserved surface formed by a of of p53-TD for the surface of p53-TD that interacts with were on of p53-TD with of Cul7-CPH The that the of Cul7-CPH are by in of the residues and for residues and they and to the and are exposed to the surface of p53. these residues are C and and have been to a site for interaction with other proteins P. A. C. W. M. Oncogene. PubMed Scopus Google Scholar, P. A. A. M. W. 1995; PubMed Scopus Google Scholar). and are also and they to the that the to the residues in p53-TD not because of W. Y. P. Nat. Biol. PubMed Scopus Google Scholar). of the small size of p53-TD and as a result of in it is that residues distinct from the binding surface may also by interaction with Cul7-CPH a complex between the p53 and the Cul7-CPH domain the of the further the NMR of the This may distinct shift are for the CPH only are for the in The interaction surface on p53-TD is formed by at least two suggesting that oligomerization may required for the interaction. To the role that oligomerization plays in p53 binding to we NMR using two and p53 and which are and forms of the p53 protein, W. Y. C. S. J. Mol. Biol. PubMed Scopus Google Scholar). shown in Fig. under the the complex was interaction with was whereas the of interaction on shift These by the of conformation three-dimensional binding surface in the P. E. C. Oncogene. PubMed Scopus Google Scholar), whereas is a that the p53-TD and in to a surface W. Y. C. S. J. Mol. Biol. PubMed Scopus Google Scholar). together that complex or tetramerization of p53. The with CPH domain with sequence to Cul7-CPH is also present within the region of PARC To these two proteins interact in the with p53, we an NMR and identified the residues in the of These were mapped a homology of the Fig. the surface for both proteins with p53 interacting residues for the The of the and the that the structure and interaction of both domains with p53 are The p53 is because of its in cancer. The TD of p53 has been in multiple of p53 function DNA subcellular and of the state of p53 to as by with and P. E. C. Oncogene. PubMed Scopus Google and in C. G. G. J. Mol. Biol. 2003; PubMed Scopus Google Scholar). domain interactions by binding to residues in the TD or because they an p53 the TD has been in interactions with C. P. A. N. W. M. Mol. Cell Biochem. 1999; PubMed Google Scholar), the protein C C. C. A. M. E. J. J. J. Biochem. PubMed Scopus Google Scholar), and the of T. N. S. T. 1996; PubMed Scopus Google a interaction between the TD and these proteins has not yet been The involvement of the TD in interactions that this domain functions not only to p53 DNA binding also to the interactions with other because of an in the binding by an in of binding in regions of the The of the TD is important for p53 regulation by other and a structure may the interaction of p53 with multiple proteins. This for the of the various that on the p53 pathway. are on the structure of p53. The ubiquitylation of p53 it to J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), and its degradation is tetramerization is M. Mol. Cell Biol. 18: PubMed Scopus Google Scholar). this we have shown that residues 360-460 domain) of Cul7 that are highly conserved within both PARC and Cul7 proteins 1) are to interact directly with the Our are with the of the Cul7-CPH domain with p53 (6Andrews P. He Y.J. Xiong Y. Oncogene. 2006; 25: 4534-4548Crossref PubMed Scopus (79) Google Scholar, 11Kasper J.S. Arai T. Decaprio J.A. Biochem. Biophys. Res. Commun. 2006; 348: 132-138Crossref PubMed Scopus (24) Google Scholar). We have solved the structure of the CPH domain of Cul7, a putative E3 ligase by NMR spectroscopy. The three-dimensional structure of the CPH domain is similar to other small interaction domains such as the KOW T. S. R. Wahl EMBO J. 2002; PubMed Scopus Google Scholar), the SH3 PubMed Scopus Google and the Tudor domain P. R. G. U. M. Nat. Biol. PubMed Scopus Google Scholar). the SH3 and Tudor domains, which bind to small the CPH domain appears to bind to an surface on a p53 Our provide novel into the interaction between Cul7 and p53 proteins. the similarity within Cul7 and PARC, we the interaction between domain with p53-TD by Our NMR and homology data that the CPH domains of Cul7 and PARC to similar in structure, and they residues that the interaction with This the that other CPH proteins may also interact with p53. the conserved residues of Cul7 and PARC CPH domains are also conserved in the protein, suggesting that this domain in HERC2 may also bind directly to p53 The region of Cul7 has been by and (6Andrews P. He Y.J. Xiong Y. Oncogene. 2006; 25: 4534-4548Crossref PubMed Scopus (79) Google Scholar, 11Kasper J.S. Arai T. Decaprio J.A. Biochem. Biophys. Res. Commun. 2006; 348: 132-138Crossref PubMed Scopus (24) Google to a with (6Andrews P. He Y.J. Xiong Y. Oncogene. 2006; 25: 4534-4548Crossref PubMed Scopus (79) Google Scholar, 11Kasper J.S. Arai T. Decaprio J.A. Biochem. Biophys. Res. Commun. 2006; 348: 132-138Crossref PubMed Scopus (24) Google Scholar), that Cul7 bind to p53 and the binding between the CPH domain and p53 involves a of interactions that on residues (see NMR Although the affinity of the CPH domain for p53 is it is to for the p53 interaction surface is highly suggesting an important the affinity of Cul7 has been shown to the CPH domain (6Andrews P. He Y.J. Xiong Y. Oncogene. 2006; 25: 4534-4548Crossref PubMed Scopus (79) Google Scholar), suggesting that domains of Cul7 may also in the interaction. such a a of the CPH domain in the in the of interactions the were also the CPH domain may provide specificity to the and domains together may to the total binding that p53 is and the interaction with Cul7-CPH is a role for Cul7 may of high levels of p53 in the The tetramerization of p53 has also been to in its P. Oncogene. PubMed Scopus Google Scholar). The that control p53 activity such as cellular and tetramerization are regulated and in The p53 nuclear export signal residues within the the of p53, the residues by the nuclear export are in the of TD, and it is that the into or is required for nuclear export (14Stommel J.M. Marchenko N.D. Jimenez G.S. Moll U.M. Hope T.J. Wahl G.M. EMBO J. 1999; 18: 1660-1672Crossref PubMed Scopus (597) Google Scholar, P. Oncogene. PubMed Scopus Google Scholar). p53 is at the p53 S.H. J. Biochem. PubMed Scopus Google Scholar). Both suggest that the subcellular localization of p53 is in by structure (14Stommel J.M. Marchenko N.D. Jimenez G.S. Moll U.M. Hope T.J. Wahl G.M. EMBO J. 1999; 18: 1660-1672Crossref PubMed Scopus (597) Google Scholar). Our that Cul7-CPH domain binds to the and forms of p53 high protein These suggest that Cul7 protein play a role in the control of p53 function by its oligomerization It has been shown that the p53 nuclear export signal p53 nuclear export and Cul7-p53 whereas the nuclear localization signal in p53 p53 nuclear and (6Andrews P. He Y.J. Xiong Y. Oncogene. 2006; 25: 4534-4548Crossref PubMed Scopus (79) Google Scholar). to PARC, which has been to bind to p53 and sequester it in the cytoplasm (10Nikolaev A.Y. Li M. Puskas N. Qin J. Gu W. Cell. 2003; 112: 29-40Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar), Cul7 has not shown cytoplasmic activity p53, it to the cytoplasmic ubiquitin ligase for p53 degradation (6Andrews P. He Y.J. Xiong Y. Oncogene. 2006; 25: 4534-4548Crossref PubMed Scopus (79) Google Scholar). the role of Cul7, in its with p53, to

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