HGNC Approved Gene Symbol: CUL2
Cytogenetic location: 10p11.21 Genomic coordinates (GRCh38): 10:35,008,551-35,127,006 (from NCBI)
Kipreos et al. (1996) identified a conserved gene family, designated cullins, with at least 5 members in nematodes, 6 in humans, and 3 in S. cerevisiae. Human CUL2 is an ortholog of nematode cul2. Michel and Xiong (1998) identified human CUL2 cDNAs and reported that the predicted protein is 745 amino acids long.
Pause et al. (1997) reported that the protein sequences of human and C. elegans cul2 are 45% identical. Using immunofluorescence, they showed that CUL2 is a cytosolic protein that can be translocated to the nucleus by VHL (608537).
Both Pause et al. (1997) and Lonergan et al. (1998) found that CUL2 specifically associates with the trimeric VHL-elongin B (600787)-elongin C (600788), or VBC, complex in vitro and in vivo. This association was disrupted by mutations in VHL that disrupt elongin binding. Nearly 70% of the naturally-occurring cancer-disposing mutations in VHL abrogate elongin binding, suggesting that binding to elongin-CUL2 complexes contributes to the ability of VHL to suppress tumor growth in vivo. Pause et al. (1997) suggested that CUL2 is a candidate tumor suppressor gene, as has been proposed for CUL1 (603134). Lonergan et al. (1998) demonstrated that formation of the VBC-CUL2 complexes is linked to the regulation of hypoxia-inducible mRNAs by VHL. They proposed a model for this regulation based on the similarity of elongin C and CUL2 to SKP1 (601434) and CUL1, which have been shown in yeast to form complexes that target specific proteins for ubiquitin-dependent proteolysis.
In C. elegans, DeRenzo et al. (2003) found that Cul2 was one of several proteins required for degradation of a class of RNA-binding germline proteins in somatic cells of the early blastomere.
UBXN7 (616379) mediates interaction of the p97 ATPase (VCP; 601023) with the transcription factor HIF1A (603348), which is actively ubiquitylated in normoxic cells by the E3 ligase CRL2, which consists of CUL2, RBX1 (603814), elongin B, and elongin C. By immunoprecipitation analysis, Bandau et al. (2012) showed that UBXN7 interacted with CUL2 in a ubiquitylation-independent manner that allowed accumulation of HIF1A. UBXN7 preferentially interacted with CUL2 that had been neddylated at lys689 and lys719. Mutation analysis indicated that the central ubiquitin interaction motif (UIM) of UBXN7 was necessary for interaction with CUL2 following NEDD8 (603171) modification. Overexpression of UBXN7 resulted in HIF1A accumulation in a UIM-dependent manner. Bandau et al. (2012) proposed that sequestration of CUL2 in its neddylated form by UBXN7 negatively regulates the ubiquitin ligase activity of the CRL2 complex. They suggested that sequestration of CUL2 by UBXN7 may also prevent recruitment of ubiquitin receptors other than p97 to nuclear HIF1A.
Clifford et al. (1999) showed that the CUL2 gene contains 21 exons ranging between 50 and 570 bp, separated by 20 introns that follow the usual GT/AG rule at the splice sites.
By fluorescence in situ hybridization, Clifford et al. (1999) mapped the CUL2 gene to 10p11.2-p11.1, a region reported to show loss of heterozygosity (LOH) in several forms of human cancer, including non-clear cell renal cell carcinoma.
Clifford et al. (1999) could demonstrate no pathogenic CUL2 mutations in 89 sporadic renal cell carcinomas analyzed.
To examine whether CUL2 plays a role in pheochromocytoma pathogenesis, Duerr et al. (1999) analyzed a series of 26 distinct tumor samples for mutations in the coding segments of the CUL2 gene. They identified no somatic pathogenic mutations in CUL2, except for 1 sporadic tumor that had a hemizygous gene deletion. The authors also identified 3 novel polymorphisms in the gene. Two variants, IVS5-6C/T and 2057G/A were overrepresented in pheochromocytoma patients compared to controls (P less than 0.005 and P less than 0.01, respectively). Although these findings suggested that CUL2 does not play a major role in the pathogenesis of pheochromocytomas, the authors concluded that further studies are needed to determine if epigenetic mechanisms are involved in its inactivation in VHL-associated tumors and the potential role for the overrepresented alleles in the pheochromocytoma group.
Bandau, S., Knebel, A., Gage, Z. O., Wood, N. T., Alexandru, G. UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1-alpha accumulation. BMC Biol. 10: 36, 2012. Note: Electronic Article. [PubMed: 22537386] [Full Text: https://doi.org/10.1186/1741-7007-10-36]
Clifford, S. C., Walsh, S., Hewson, K., Green, E. K., Brinke, A., Green, P. M., Gianelli, F., Eng, C., Maher, E. R. 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. Genes Chromosomes Cancer 26: 20-28, 1999. [PubMed: 10441001]
DeRenzo, C., Reese, K. J., Seydoux, G. Exclusion of germ plasm proteins from somatic lineages by cullin-dependent degradation. Nature 424: 685-689, 2003. [PubMed: 12894212] [Full Text: https://doi.org/10.1038/nature01887]
Duerr, E.-M., Gimm, O., Neuberg, D. S., Kum, J. B., Clifford, S. C., Toledo, S. P. A., Maher, E. R., Dahia, P. L. M., Eng, C. Differences in allelic distribution of two polymorphisms in the VHL-associated gene CUL2 in pheochromocytoma patients without somatic CUL2 mutations. J. Clin. Endocr. Metab. 84: 3207-3211, 1999. [PubMed: 10487688] [Full Text: https://doi.org/10.1210/jcem.84.9.5961]
Kipreos, E. T., Lander, L. E., Wing, J. P., He, W. W., Hedgecock, E. M. cul-1 is required for cell cycle exit in C. elegans and identifies a novel gene family. Cell 85: 829-839, 1996. [PubMed: 8681378] [Full Text: https://doi.org/10.1016/s0092-8674(00)81267-2]
Lonergan, K. M., Iliopoulos, O., Ohh, M., Kamura, T., Conaway, R. C., Conaway, J. W., Kaelin, W. G., Jr. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Molec. Cell. Biol. 18: 732-741, 1998. [PubMed: 9447969] [Full Text: https://doi.org/10.1128/MCB.18.2.732]
Michel, J. J., Xiong, Y. Human CUL-1, but not other cullin family members, selectively interacts with SKP1 to form a complex with SKP2 and cyclin A. Cell Growth Differ. 9: 435-449, 1998. [PubMed: 9663463]
Pause, A., Lee, S., Worrell, R. A., Chen, D. Y. T., Burgess, W. H., Linehan, W. M., Klausner, R. D. The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc. Nat. Acad. Sci. 94: 2156-2161, 1997. [PubMed: 9122164] [Full Text: https://doi.org/10.1073/pnas.94.6.2156]