Disease relevance of CDC34

• The ubiquitin-conjugating enzyme CDC34 (UBC3) is linked to cell cycle progression in diverse cell types; however, its role in multiple myeloma (MM) pathogenesis is unclear [1].
• Expression and localization of the CDC34 ubiquitin-conjugating enzyme in pediatric acute lymphoblastic leukemia [2].
• The data presented in this report are incompatible with the hypothesis that ICP0 induces the degradation of cdc34 and thereby stabilizes cyclins D1 and D3 during HSV-1 infection [3].
• Herpes simplex virus 1 mutant in which the ICP0 HUL-1 E3 ubiquitin ligase site is disrupted stabilizes cdc34 but degrades D-type cyclins and exhibits diminished neurotoxicity [4].
• The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53 [5].

High impact information on CDC34

• In this issue of Cell, Deffenbaugh et al. provide experimental support for a model in which the dynamic release of the ubiquitin-charged E2 Cdc34 from its primary binding site within the rigid cradle-like SCF E3 complex allows for unexpected spatial flexibility to assemble a polyubiquitin chain [6].
• In vitro and in vivo, forced expression of UCP boosts tumor-cell proliferation, invasion and metastasis through effects on the pVHL-HIF pathway [7].
• UCP level correlates inversely with pVHL level in most tumor cell lines [7].
• UCP is detected coincidently with HIF-1alpha in human primary liver, colon and breast tumors, and metastatic cholangiocarcinoma and colon cancer cells [7].
• These findings identify a physiologic role for c-IAP1 and define a mechanism by which TNF-RII-regulated ubiquitin protein ligase activity can potentiate TNF-induced apoptosis [8].

Chemical compound and disease context of CDC34

• Mutations in Parkin (a ubiquitin protein ligase) are involved in autosomal recessive juvenile parkinsonism, but it is not known how they cause nigral cell death [9].
• Glucocorticoids have been suggested to activate this system in sepsis, while in cancer cachexia a tumour-produced sulphated glycoprotein, proteolysis-inducing factor, induces protein catabolism in skeletal muscle by increasing expression of proteasome subunits and the ubiquitin carrier protein, E2(14k) [10].

Biological context of CDC34

• One pathway, requiring CDC34, initiates DNA replication by degrading a CDK inhibitor [11].
• Cloning of the human homolog of the CDC34 cell cycle gene by complementation in yeast [12].
• In a screen designed to isolate human cDNAs that complement a yeast G2 phase checkpoint mutation (mec1), we isolated a cDNA homologous to the Saccharomyces cerevisiae CDC34 gene [12].
• Phosphorylation of CDC34 by the associated kinase maps predominantly to residues 203 and 222 [13].
• Finally, we find that in anaphase and not during early stages of mitosis, CDC34 colocalizes with (beta)-tubulin at the mitotic spindle, implying that it may contribute to spindle function at later stages of mitosis [14].

Anatomical context of CDC34

• The human CDC34 gene is expressed in multiple cell lines as a unique species and Southern blot analysis reveals evidence for a single gene that is highly conserved in higher eukaryotes [12].
• The Cdc34 and Rad6B proteins are significantly elevated in meiotic and postmeiotic haploid germ cells when chromatin modifications occur [15].
• CDC34 protein (but not mRNA) was also increased in T-cell ALL compared with pre-B-cell ALL cell lines [2].
• Negative regulation of FcepsilonRI-mediated mast cell activation by a ubiquitin-protein ligase Cbl-b [16].
• Characterization of rat100, a 300-kilodalton ubiquitin-protein ligase induced in germ cells of the rat testis and similar to the Drosophila hyperplastic discs gene [17].

Associations of CDC34 with chemical compounds

• We have also identified a kinase activity associated with CDC34 in proliferating cells, and we show that this kinase is sensitive to heparin and can utilize GTP, strongly suggesting it is CK2 [13].
• Human Cdc34 and Rad6B ubiquitin-conjugating enzymes target repressors of cyclic AMP-induced transcription for proteolysis [15].
• Blockade of ubiquitin-conjugating enzyme CDC34 enhances anti-myeloma activity of Bortezomib/Proteasome inhibitor PS-341 [1].
• Blocking CDC34 using a dominant-negative strategy enhances the anti-MM activity of Bortezomib/Proteasome inhibitor PS-341, dexamethasone (Dex) and 2-Methoxyestradiol (2ME2) [1].
• Part of the stimulatory effect of aldosterone on ENaC is mediated by the induction of serum- and glucocorticoid-regulated kinase 1 (Sgk1), a kinase that interferes with the ubiquitylation of ENaC by ubiquitin-protein ligase Nedd4-2 [18].

Physical interactions of CDC34

• Active site residues and amino acid specificity of the ubiquitin carrier protein-binding RING-H2 finger domain [19].

Regulatory relationships of CDC34

• The human ubiquitin-conjugating enzyme Cdc34 controls cellular proliferation through regulation of p27Kip1 protein levels [20].
• The ordered activation of the ubiquitin protein ligase anaphase-promoting complex (APC) or cyclosome by CDC20 in metaphase and by CDH1 in telophase is essential for anaphase and for exit from mitosis, respectively [21].
• Elevating the level of Cdc34/Ubc3 ubiquitin-conjugating enzyme in mitosis inhibits association of CENP-E with kinetochores and blocks the metaphase alignment of chromosomes [22].

Other interactions of CDC34

• Consistent with these results, the endogenous ICER protein is elevated in cells which are null for murine Rad6B (mHR6B-/-) or transfected with dominant negative and antisense constructs of human CDC34 [15].
• Phosphorylation of the human ubiquitin-conjugating enzyme, CDC34, by casein kinase 2 [13].
• SCFHOS-ROC1 binds IKK beta-phosphorylated I kappa B alpha and catalyzes its ubiquitination in the presence of ubiquitin, E1, and Cdc34 [23].
• We have further demonstrated that separate regions within the human Cdc34 C-terminal tail are responsible for multiubiquitin chain assembly and for physical interactions with the Nedd8-conjugated ROC1-CUL1 to assemble extensive ubiquitin polymers [24].
• Here, we show that antisense oligonucleotides targeting the human ubiquitin-conjugating enzyme Cdc34 downregulate its expression, inhibit the degradation of p27Kip1, and prevent cellular proliferation [20].

Analytical, diagnostic and therapeutic context of CDC34

• Immunofluorescence experiments reveal that during interphase, endogenous CDC34 is localized to distinct speckles in both the nucleus and the cytoplasm [14].
• Immunohistochemistry and cellular fractionation reveals a heterogeneous CDC34 expression pattern including cells containing primarily cytoplasmic or nuclear protein [2].
• The AP20187-induced dimeric form of FKBP-Cdc34 was substantially more active than the monomer in catalyzing Ub-Ub ligation [25].
• Elevation of Cdc34 protein levels by microinjection of bacterially expressed Cdc34 into mammalian cells at prophase inhibited chromosome congression to the metaphase plate with many chromosomes remaining near the spindle poles [22].

References