Disease relevance of CUL1

• Primate lentiviral virion infectivity factors are substrate receptors that assemble with cullin 5-E3 ligase through a HCCH motif to suppress APOBEC3G [1].
• Human immunodeficiency virus-1 (HIV-1) Vif overcomes the anti-viral activity of APOBEC3G by targeting it for ubiquitination via a Cullin 5-ElonginB-ElonginC (Cul5-EloBC) E3 ligase [2].
• Myxoma virus M-T5 protects infected cells from the stress of cell cycle arrest through its interaction with host cell cullin-1 [3].
• One of the cullin genes, Cul-4A, is amplified and overexpressed in breast cancer cells [4].

High impact information on CUL1

• Finally, components of both the APC and the SCF E3 ubiquitin-ligase complex contain several conserved sequence motifs, including WD-40 repeats and cullin homology domains, which suggest that both complexes may use a similar mechanism for substrate ubiquitination [5].
• SCF and Cullin/Ring H2-based ubiquitin ligases [6].
• Finally, we show that Ddb1/Csn1/Cullin 4-mediated Spd1 degradation becomes essential when cells differentiate into meiosis [7].
• The human UV-damaged DNA-binding protein Ddb1 associates with cullin 4 ubiquitin ligases implicated in nucleotide excision repair (NER) [7].
• These results suggest that Ddb1, along with Cullin 4 and the signalosome, constitute a major pathway controlling genome stability, repair, and differentiation via RNR regulation [7].

Biological context of CUL1

• We report the isolation of a CUL1 binding protein, p120(CAND1) [8].
• The cullin-containing ubiquitin-protein isopeptide ligases (E3s) play an important role in regulating the abundance of key proteins involved in cellular processes such as cell cycle and cytokine signaling [9].
• As shown for other E3 ubiquitin ligases, dimerization may play a role in regulating the activity of cullin-based E3 ligases [10].
• Suppression of CUL1 expression had influence on the phenotype of T-cell line, that is, it inhibited IL-8 induction, which is known to play an important role in the migration of inflammatory cells into the affected area seen in RA [11].
• Our data suggest that the regulation of CUL1 expression in immunological tissues may affect the susceptibility of RA via altering lymphocyte signal transduction [11].

Anatomical context of CUL1

• We found that the supplementation of Skp2-Skp1 and substrate (along with further components necessary for substrate presentation to the ubiquitin ligase) to extracts of HeLa cells synergistically increased levels of neddylated Cul1 [12].
• To characterize this family of E3 ligases in intact cells, we generated a cell line with tetracycline-inducible expression of a dominant-negative mutant of the Nedd8-conjugating enzyme Ubc12, a reported inhibitor of cullin neddylation [10].
• Histological evaluation of tonsils indicated that CUL1 protein expression was relatively specific for maturing germinal centers [11].
• Quantitative expression analysis revealed that CUL1 mRNA was highly detected in lymphoid tissues including spleen and tonsil, and was specifically expressed in T and B lymphocytes in fractionated peripheral leukocytes [11].
• By using a mRNA differential display technique to search for salicylate suppressible genes, we identified a cDNA in human foreskin fibroblasts, which by GenBankTM DNA data base search shows sequence homology to the recently reported cullin/Cdc53 (CUL) family genes, especially CUL-3 [13].

Associations of CUL1 with chemical compounds

• Two, a large body of work has helped elucidate the molecular details underlying the Nedd8 modification reaction, which results in covalent conjugation of a Nedd8 moiety onto a conserved cullin lysine residue [14].
• Arabidopsis ETA2, an apparent ortholog of the human cullin-interacting protein CAND1, is required for auxin responses mediated by the SCF(TIR1) ubiquitin ligase [15].
• CUL7: A DOC domain-containing cullin selectively binds Skp1.Fbx29 to form an SCF-like complex [16].
• Cloning and expression analysis of a novel salicylate suppressible gene, Hs-CUL-3, a member of cullin/Cdc53 family [13].
• Substitution of D97 with each of the other 19 amino acids demonstrates that aspartate is superior to cysteine in cullin NEDDylation [17].

Physical interactions of CUL1

• CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex [8].
• SCF (Skp1/Cullin/F-box protein) complexes and anaphase-promoting complexes (APC) represent two major classes of ubiquitin ligases whose activities are thought to regulate primarily the G1/S and metaphase/anaphase cell-cycle transitions, respectively [18].
• Interestingly, SKR-3 could interact with both CUL-1 and its close paralog CUL-6 [19].
• CUL-1 was found to interact with SKR-1, -2, -3, -7, -8, and -10 in the yeast two-hybrid system [19].

Regulatory relationships of CUL1

• Covalent modification of cullins by the ubiquitin-like protein NEDD8 activates cullin ligases through an as yet undefined mechanism [20].
• CAND1 enhances deneddylation of CUL1 by COP9 signalosome [21].
• Considered with evidence that the distinct Cullin-1 based SCF(beta-TrCP)complex regulates beta-catenin stability, our data on the stability of Dishevelled demonstrates that two distinct ubiquitin ligase complexes regulate the Wnt-beta-catenin pathway [22].
• COMMD1 promotes the ubiquitination of NF-kappaB subunits through a cullin-containing ubiquitin ligase [23].

Other interactions of CUL1

• Neddylation of CUL1 or the presence of SKP1 and ATP causes CAND1 dissociation [8].
• At elevated concentrations, DEN1 is able to complete the removal of Nedd8 from CUL1 [24].
• In a search for proteins involved in regulation of cullin-containing E3 ubiquitin ligases we immunopurified CUL4B-containing complex from HeLa cells and identified TIP120A as an associated protein by mass spectrometry [9].
• The sequence flanking the RING finger in ROC1 did not contribute to UBCH5c activation, but was required for binding with CUL1 [25].
• Cul3, but not Cul1 homooligomerization is dependent on substrate recognition subunit dimer formation [10].

Analytical, diagnostic and therapeutic context of CUL1

• Immunoblotting and in vitro ubiquitination assays indicated that the expression of Cul1 and Skp2 and ubiquitination activity toward p27(Kip1) were not regulated by NSAIDs [26].
• The expression of mRNA for other CUL family members (CUL-1, -2, -3, -4A, and -4B) in these cells was evaluated by RT-PCR [27].

References