Disease relevance of UBE2L3

• The protein also exhibits very strong homology to a rabbit protein, E2-F1, which mediates p53 degradation driven by papilloma virus E6 protein in vitro [1].
• We show that E2F1 expression is low in benign and localized prostate cancer, modestly elevated in metastatic lymph nodes from hormone-na??ve patients, and significantly elevated in metastatic tissues from hormone-resistant prostate cancer patients (P = 0.0006) [2].
• Two separate sets of primers were used that recognized the regulatory retinoblastoma (Rb) protein-binding region and the functional DNA-binding region of E2F1 [3].

High impact information on UBE2L3

• The crystal structure of the E6AP hect domain bound to the UbcH7 ubiquitin-conjugating enzyme (E2) reveals the determinants of E2-E3 specificity and provides insights into the transfer of ubiquitin from the E2 to the E3 [4].
• Suppression of p85Cool-1/betaPix expression restores UbcH7 raft localization and Vav ubiquitination and diminishes Cdc42 activity [5].
• Nef-mediated lipid raft exclusion of UbcH7 inhibits Cbl activity in T cells to positively regulate signaling [5].
• Regulation of E2F1-mediated apoptosis is essential for proper cellular growth [6].
• Correlative evidence showed the failure of hSpry2DeltaN11 and mSpry4, both deficient in c-Cbl binding, to instigate these effects. hSpry2 interacts specifically with the c-Cbl RING finger domain and displaces UbcH7 from its binding site on the E3 ligase [7].

Biological context of UBE2L3

• We have identified a human gene, UBE2L3, localized on Chromosome (Chr) 22q11 [8].
• In contrast to the intronless UBE2L1 gene, the coding sequence of UBE2L3 is interrupted by three large introns [8].
• Protein:DNA interaction studies confirmed the presence of binding sites for the transcription factors AP2 and Sp1 in the UBE2L3 minimal promoter [9].
• We investigated the role of the ubiquitin-conjugating enzyme UBCH7 in nuclear receptor transactivation [10].
• Human homologue of Drosophila ariadne (HHARI) is a RING-IBR-RING domain protein identified through its ability to bind the human ubiquitin-conjugating enzyme, UbcH7 [11].

Anatomical context of UBE2L3

• By comparison, UBCH7 (an ubiquitin-conjugating E2) is 10-fold more abundant in Jurkat cells and 30-fold more abundant than E2 UBCH5A [12].
• We show that exogenous expression of E2F1 significantly inhibited AR mRNA and AR protein levels in prostate epithelial cells [2].
• We show that Hace1 protein possesses intrinsic ubiquitin ligase activity, utilizes UbcH7 as a candidate partner E2 enzyme and localizes predominantly to the endoplasmic reticulum [13].
• RESULTS: Ubiquitin and UbcH7 were observed in both nucleus and cytoplasm of normal, "premalignant" and malignant tissues of oral mucosa using immunoelectron microscopy [14].
• Melanin accumulation accelerates melanocyte senescence by a mechanism involving p16INK4a/CDK4/pRB and E2F1 [15].

Associations of UBE2L3 with chemical compounds

• The ubiquitin-conjugating enzyme UBCH7 acts as a coactivator for steroid hormone receptors [10].
• Biochemically, parkin appeared most enriched in cytosolic and postsynaptic fractions of adult rat brain, but also in purified, alpha S-rich presynaptic elements that additionally contained parkin's E2-binding partner, UbcH7 [16].

Physical interactions of UBE2L3

• Dorfin bound specifically with human ubiquitin-conjugating enzymes UbcH7 and UbcH8 through the RING-finger/IBR domain [17].
• UbcH7 interacts with the glucocorticoid receptor and mediates receptor autoregulation [18].

Co-localisations of UBE2L3

• We now demonstrate that HHARI interacts and co-localizes with UbcH7 in mammalian cells, particularly in the perinuclear region [19].

Other interactions of UBE2L3

• Comparison of the genomic organization of UBE2L6 with UBE2L3 demonstrates that these genes remain highly conserved at the genomic as well as at the protein level [20].
• We recently reported the identification of a RING finger-containing protein, HHARI (human homologue of Drosophila ariadne), which binds to the human ubiquitin-conjugating enzyme UbcH7 in vitro [19].
• Furthermore, nuclear localization of N-terminal deletion mutant Nedd4 enabled us to investigate the interaction between Nedd4 and E2 enzyme (Ubc4 or UbcH7) in the cell [21].
• Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade [4].
• To determine whether NKLAM functions as an E3 ligase, we performed coimmunoprecipitation binding assays with ubiquitin conjugates (Ubcs) UbcH7, UbcH8, and UbcH10 [22].

Analytical, diagnostic and therapeutic context of UBE2L3

• 3. Using chromosome-specific vectorette PCR, we have determined the intron/exon structure of UBE2L3 [8].
• Here we analysed by in situ hybridization the expression of mRNAs for parkin and UbcR7 (rat orthologue of human UbcH7) in the developing rat brain [23].
• In this study, we examined the expression of E2F1 in 667 prostate tissue cores and compared it with the expression of the androgen receptor (AR), a marker of prostate epithelial differentiation, using tissue microarray analysis [2].

References