Disease relevance of CUL5

• Polymorphisms of CUL5 are associated with CD4+ T cell loss in HIV-1 infected individuals [1].
• We have localized the human homolog of the rabbit vasopressin-activated calcium-mobilizing receptor VACM-1 to a region close to the gene for ataxia telangiectasia ATM on chromosome 11q22-23 [2].
• T47D breast cancer cell growth is inhibited by expression of VACM-1, a cul-5 gene [3].
• Vasopressin-activated calcium-mobilizing (VACM-1), a cul-5 gene, is localized on chromosome 11q22-23 close to the gene for Ataxia Telangiectasia in a region associated with a loss of heterozygosity in breast cancer tumor samples [3].
• We examined the effect of genetic polymorphisms in the CUL5 gene (encoding Cullin 5 protein) on AIDS disease progression in five HIV-1 longitudinal cohorts [1].

High impact information on CUL5

• Therefore, selective assembly with Cul5 versus Cul2 E3 may require protein interfaces besides the SOCS-box-ElonginC interaction [4].
• This new motif was necessary but insufficient for interaction with Cul5-ElonginB-ElonginC, as two highly conserved Cys residues outside the SOCS box were required to interact with Cul5 but not ElonginC [4].
• However, although the nature and expression of both vasopressin V1 receptors and human VACM are apparently unaffected by dedifferentiation in SCCL, only the abnormal (and probably nonfunctional) form of the V2 receptor could be demonstrated in variant cell line NCI H82 [5].
• Identification and analysis of expression of human VACM-1, a cullin gene family member located on chromosome 11q22-23 [2].
• We have determined the complete amino acid sequence of the human Hs-VACM-1 protein, which is 780 amino acids long [2].

Chemical compound and disease context of CUL5

• VACM-1 activation in fibroblasts was insensitive to phosphatidylinositol-3-kinase inhibitor LY294002, but was inhibited by pertussis toxin, suggesting that activation of VACM-1 could be mediated by a G protein-coupled receptor [6].

Biological context of CUL5

• A phylogenetic network analysis revealed that CUL5 haplotypes were grouped into two clusters of evolutionarily related haplotypes [1].
• The Hs-VACM-1 gene has homology with the Caenorhabditis elegans gene Ce-cul-5, a member of a family of cullin genes that are involved in cell cycle regulation and that might, when mutated, contribute to tumor progression [2].
• The Vif binding site maps to the first cullin repeat in the N terminus of Cul5 [7].
• K28 shows sequence homology to the Rab GTP binding protein family and gene 6.82 homology to the rabbit vasopressin activated calcium mobilizing receptor, while gene F37 has no homology to any known sequence in the database [8].
• Overexpressing VACM-1 significantly attenuated cellular proliferation and MAPK phosphorylation when compared to the control cells [3].

Anatomical context of CUL5

• To determine if the ability of E1B-55K and E4orf6 to stimulate viral late mRNA nuclear export requires the ubiquitin-protein ligase activity of this viral ubiquitin-protein ligase complex, we designed and expressed a dominant-negative mutant form of cullin 5 in HeLa cells before infection with wild-type Ad5 or the E1B-55K null mutant dl1520 [9].
• To further examine the biological role of VACM-1, we studied the effect of VACM-1 and S730AVACM-1 proteins on cellular proliferation and gene expression in Chinese hamster ovary and COS-1 cells [10].
• Expression of VACM-1 protein in cultured rat adrenal endothelial cells is linked to the cell cycle [11].
• VACM-1 protein virtually disappears during the S phase and localizes to the cytosol during cell division and to the cell membrane at the completion of cytokinesis [11].
• RESULTS: CUL-5 is expressed at the mRNA and protein levels by breast epithelial cells (HMEC, MCF-10A) and breast cancer cells (MCF-7, MDA-MB-231) [12].

Associations of CUL5 with chemical compounds

• Mutations of His/Cys residues in the HCCH motif impair zinc coordination, Cul5 binding, and APOBEC3G degradation [7].
• The protein kinase C specific inhibitor Gö-6983 further enhanced the inhibitory effect of VACM-1 on AVP-stimulated cAMP production [13].
• A randomized trial comparing Vincristine, Adriamycin, Cyclophosphamide (VAC) with or without Methotrexate with citrovorum factor rescue (VACM) was performed in 64 patients with metastatic postmenopausal mammary carcinoma [14].

Physical interactions of CUL5

• These data suggest that the zinc-binding region in Vif is a novel cullin interaction domain that mediates selective binding to Cul5 [7].
• The dominant-negative cullin 5 protein stabilized p53 and the MRN complex, indicating that it inhibited the viral ubiquitin-protein ligase but had no effect on viral early mRNA synthesis, early protein synthesis, or viral DNA replication [9].
• Vasopressin-activated Ca(2+)-mobilizing (VACM-1) receptor binds arginine vasopressin (AVP) but does not have amino acid sequence homology with the traditional AVP receptors [13].

Regulatory relationships of CUL5

• Mutations of conserved hydrophobic residues (Ile-120, Ala-123, and Leu-124) located between the two Cys residues in the HCCH motif disrupt binding of the zinc-coordinating region to Cul5 and inhibit APOBEC3G degradation [7].
• Screening with the Human PathwayFinder-1 GEArray system and subsequent Western blot analysis demonstrated that VACM-1 induces p53 mRNA and protein expression [10].

Other interactions of CUL5

• These findings suggest that the E3 ubiquitin ligase activity of the Vif-BC-Cul5 complex is essential for Vif function against APOBEC3G [15].
• At present, the determinants of Cul2 vs. Cul5 specificity for the BC-box-containing receptors are poorly defined [16].
• Zinc chelation had no effect on cellular Cul5-SOCS3 E3 ligase assembly, suggesting that zinc-dependent E3 ligase assembly may be unique to HIV-1 Vif, representing a new target for novel drug design [17].
• The contact with knitted Dacron did not induce significant variations of ICAM-1 and VACM-1 [18].
• At 4 h ICAM-1 and E-selectin, but not VACM-1, were stimulated by both IL-1beta and TNF-alpha [19].

Analytical, diagnostic and therapeutic context of CUL5

• Immunocytochemistry studies demonstrated that VACM-1 was expressed in 0.6-6% of the T47D cells and localized to the nucleus of mitotic cells [3].
• RT-PCR experiments show the expression of V1a, V1b, V2 and vasopressin-activated calcium-mobilizing (VACM) receptors mRNAs [20].
• To characterize the VACM-1 receptor, we examined its tissue-specific expression using Northern blot, RT-PCR, and immunostaining analyses [21].
• DESIGN AND METHODS: To clarify this issue, we evaluated the effect of C-peptide on VACM-1 RNA (measured by semiquantitative RT-PCR) and protein expression (measured by immunoblotting) in human skin fibroblasts (where a specific binding of C-peptide was demonstrated) and in human mesangial cells, the cellular target of diabetic nephropathy [6].
• Combination chemotherapy in advanced postmenopausal mammary carcinoma. A comparison between VAC and VACM therapy [14].

References