Disease relevance of CUL2

• To examine whether CUL2 plays a role in pheochromocytoma pathogenesis, we analyzed a series of 26 distinct tumor samples for mutations in the whole coding region of this gene [1].
• Familial clear cell renal cell carcinoma (FCRC): clinical features and mutation analysis of the VHL, MET, and CUL2 candidate genes [2].
• Four candidate tumour markers, Laminin Receptor 1, Endothelin 2, Von Hippel Lindau Binding protein 1 and Cullin 2, have been selected from genes that were differentially expressed in the uveal melanoma cell lines compared to the normal uveal melanocytes [3].

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

• Immunofluorescence studies show Hs-CUL-2 to be a cytosolic protein that can be translocated to the nucleus by pVHL [7].

References