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Gene Review

CUL2  -  cullin 2

Homo sapiens

Synonyms: CUL-2, Cullin-2
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Disease relevance of CUL2


High impact information on CUL2

  • Therefore, selective assembly with Cul5 versus Cul2 E3 may require protein interfaces besides the SOCS-box-ElonginC interaction [4].
  • The human cullin protein CUL-2 functions in a ubiquitin-ligase complex with the von Hippel-Lindau (VHL) tumour suppressor protein [5].
  • CUL-2 is required for the G1-to-S-phase transition and mitotic chromosome condensation in Caenorhabditis elegans [5].
  • COMMD1 binds to Cul2 in a stimulus-dependent manner and serves to facilitate substrate binding to the ligase by stabilizing the interaction between SOCS1 and RelA [6].
  • Here, Hs-CUL-2, a member of the recently identified multigene family, the cullins, is shown to specifically associate with the trimeric pVHL-elongin B-C (VBC) complex in vitro and in vivo [7].

Biological context of CUL2

  • However, CUL2 remains a candidate TSG for other tumor types demonstrating 10p LOH [8].
  • There were no somatic pathogenic mutations in CUL2, except for 1 sporadic tumor that had a hemizygous gene deletion [1].
  • Recently, a putative tumor suppressor gene has been identified, CUL2, whose product has been shown to interact with the VHL tumor suppressor [1].
  • Size exclusion column chromatography and deletion mutant analysis suggest that VHL-GFP does not require assembly with one of its associated proteins, cullin-2, to engage in nuclear export [9].
  • The von Hippel-Lindau tumour suppressor gene product (pVHL) associates with the elongin B and C and Cul2 proteins to form a ubiquitin-ligase complex (VCBC) [10].

Associations of CUL2 with chemical compounds

  • Like VHL, VHL-GFP binds to elongins B and C and Cullin-2 and regulates target gene product levels, including levels of vascular endothelial growth factor and glucose transporter 1 [11].
  • Furthermore, fluorescence spectroscopy revealed that only Co(2+) and Ni(2+) have the binding activity to cullin-2, but other metal ions, including Cu(2+), Ca(2+), Mg(2+), Mn(2+), and Zn(2+), did not [12].
  • In addition to known Ni-binding molecules such as tubulin, actin or cullin-2, we unexpectedly discovered that at least nine of these 22 proteins belong to stress-inducible heat shock proteins or chaperonins [13].

Physical interactions of CUL2

  • VHL forms a multimeric complex with two subunits (B and C) of the SIII (elongin) transcriptional elongation complex and CUL2, a member of the cullin family [8].
  • Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2 [14].

Regulatory relationships of CUL2

  • Most pathogenic VHL mutations inhibit formation of the VHL/elonginB+C/CUL2 complex [8].

Other interactions of CUL2

  • One model, which remains to be tested, is that the binding of pVHL to elongins B/C and Cul2 affects the ubiquitination of RNA-binding proteins that regulate the stability of hypoxia-inducible mRNAs [15].
  • Elongin C and Cul2, based on their homology with Skp1 and Cdc53, respectively, are suspected of targeting certain proteins for covalent modification with ubiquitin and hence for degradation [15].
  • Taken together, the VBC complex appears to have ligase activity in the conjugation of NEDD8 to Cul-2 [16].
  • At present, the determinants of Cul2 vs. Cul5 specificity for the BC-box-containing receptors are poorly defined [17].
  • Exon 3-encoded alpha-helical domain is required for VHL complex formation with BC/cullin-2 and E3 ubiquitin ligase activity, for binding to HIFalpha/fibronectin, but this domain is not essential for transcription-dependent nuclear/cytoplasmic trafficking [18].

Analytical, diagnostic and therapeutic context of CUL2


  1. Differences in allelic distribution of two polymorphisms in the VHL-associated gene CUL2 in pheochromocytoma patients without somatic CUL2 mutations. Duerr, E.M., Gimm, O., Neuberg, D.S., Kum, J.B., Clifford, S.C., Toledo, S.P., Maher, E.R., Dahia, P.L., Eng, C. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  2. Familial clear cell renal cell carcinoma (FCRC): clinical features and mutation analysis of the VHL, MET, and CUL2 candidate genes. Woodward, E.R., Clifford, S.C., Astuti, D., Affara, N.A., Maher, E.R. J. Med. Genet. (2000) [Pubmed]
  3. Gene expression profiling identifies tumour markers potentially playing a role in uveal melanoma development. Zuidervaart, W., van der Velden, P.A., Hurks, M.H., van Nieuwpoort, F.A., Out-Luiting, C.J., Singh, A.D., Frants, R.R., Jager, M.J., Gruis, N.A. Br. J. Cancer (2003) [Pubmed]
  4. Selective assembly of HIV-1 Vif-Cul5-ElonginB-ElonginC E3 ubiquitin ligase complex through a novel SOCS box and upstream cysteines. Yu, Y., Xiao, Z., Ehrlich, E.S., Yu, X., Yu, X.F. Genes Dev. (2004) [Pubmed]
  5. CUL-2 is required for the G1-to-S-phase transition and mitotic chromosome condensation in Caenorhabditis elegans. Feng, H., Zhong, W., Punkosdy, G., Gu, S., Zhou, L., Seabolt, E.K., Kipreos, E.T. Nat. Cell Biol. (1999) [Pubmed]
  6. COMMD1 promotes the ubiquitination of NF-kappaB subunits through a cullin-containing ubiquitin ligase. Maine, G.N., Mao, X., Komarck, C.M., Burstein, E. EMBO J. (2007) [Pubmed]
  7. The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Pause, A., Lee, S., Worrell, R.A., Chen, D.Y., Burgess, W.H., Linehan, W.M., Klausner, R.D. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  8. Genomic organization and chromosomal localization of the human CUL2 gene and the role of von Hippel-Lindau tumor suppressor-binding protein (CUL2 and VBP1) mutation and loss in renal-cell carcinoma development. Clifford, S.C., Walsh, S., Hewson, K., Green, E.K., Brinke, A., Green, P.M., Gianelli, F., Eng, C., Maher, E.R. Genes Chromosomes Cancer (1999) [Pubmed]
  9. Ran-mediated nuclear export of the von Hippel-Lindau tumor suppressor protein occurs independently of its assembly with cullin-2. Groulx, I., Bonicalzi, M.E., Lee, S. J. Biol. Chem. (2000) [Pubmed]
  10. Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. Clifford, S.C., Cockman, M.E., Smallwood, A.C., Mole, D.R., Woodward, E.R., Maxwell, P.H., Ratcliffe, P.J., Maher, E.R. Hum. Mol. Genet. (2001) [Pubmed]
  11. Transcription-dependent nuclear-cytoplasmic trafficking is required for the function of the von Hippel-Lindau tumor suppressor protein. Lee, S., Neumann, M., Stearman, R., Stauber, R., Pause, A., Pavlakis, G.N., Klausner, R.D. Mol. Cell. Biol. (1999) [Pubmed]
  12. Cobalt- and nickel-binding property of cullin-2. Kanaya, K., Tsai, A.L., Kamitani, T. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  13. Subproteomic analysis of metal-interacting proteins in human B cells. Heiss, K., Junkes, C., Guerreiro, N., Swamy, M., Camacho-Carvajal, M.M., Schamel, W.W., Haidl, I.D., Wild, D., Weltzien, H.U., Thierse, H.J. Proteomics (2005) [Pubmed]
  14. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Lonergan, K.M., Iliopoulos, O., Ohh, M., Kamura, T., Conaway, R.C., Conaway, J.W., Kaelin, W.G. Mol. Cell. Biol. (1998) [Pubmed]
  15. von Hippel-Lindau disease. Maher, E.R., Kaelin, W.G. Medicine (Baltimore) (1997) [Pubmed]
  16. The von Hippel-Lindau tumor suppressor gene product promotes, but is not essential for, NEDD8 conjugation to cullin-2. Wada, H., Yeh, E.T., Kamitani, T. J. Biol. Chem. (1999) [Pubmed]
  17. Primate lentiviral virion infectivity factors are substrate receptors that assemble with cullin 5-E3 ligase through a HCCH motif to suppress APOBEC3G. Luo, K., Xiao, Z., Ehrlich, E., Yu, Y., Liu, B., Zheng, S., Yu, X.F. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  18. Role of exon 2-encoded beta -domain of the von Hippel-Lindau tumor suppressor protein. Bonicalzi, M.E., Groulx, I., de Paulsen N, n.u.l.l., Lee, S. J. Biol. Chem. (2001) [Pubmed]
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