Background
The enzymes of the ubiquitylation pathway play a pivotal role in a number of cellular processes including the regulated and targeted proteasomal degradation of substrate proteins. Three classes of enzymes are involved in the process of ubiquitylation; activating enzymes (E1s), conjugating enzymes (E2s) and protein ligases (E3s). UBE2D3 is a member of the E2 ubiquitin-conjugating enzyme family and cloning of the gene was first described by Jensen et al. (1995). Human UBE2D3 shares 94% and 79% sequence identity with the Drosophila and S. cerevisiae homologues respectively. The E3 ligase E6AP mediates the conjugation of ubiquitin to targets such as p53 via UBE2D3 (Jensen et al., 1995). Upregulation of UBE2D3 following treatment with Retinoic Acid (RA) has been shown to induce differentiation and growth arrest in NB4 human promyelocytic cells. UBE2D3 also associates with Cyclin D1 and mediates retinoic acid induced cyclin D1 degradation (Hattori et al., 2007). Activation of the IKK complex is mediated by unanchored polyubiquitin chains formed by UBE2D3 and TRAF6 (Xia et al., 2009). Zipper-Interacting Protein Kinase (ZIPK) is a serine/threonine kinase implicated in cell death and transcriptional regulation, UBE2D3 induces ZIPK accumulation in promyelocytic leukaemia protein nuclear bodies resulting in their ubiquitylation (Ohbayashi et al., 2008). Meibomian Cell Carcinoma (MCC) is a malignant tumour of the meibomian glands located in the eyelids. UBE2D3 has been identified by RT/PCR as one of five genes found to be upregulated in MCC tumours (Kumar et al., 2007).
References
Hattori H, Zhang X, Jia Y, Subramanian KK, Jo H, Loison F, Newburger PE, Luo HR (2007) RNAi screen identifies UBE2D3 as a mediator of all-trans retinoic acidinduced cell growth arrest in human acute promyelocytic NB4 cells. Blood 110, 640-50.
Jensen JP, Bates PW, Yang M, Vierstra RD, Weissman AM (1995) Identification of a family of closely related human ubiquitin conjugating enzymes. J Biol Chem 270, 30408-14.
Kumar A, Kumar Dorairaj S, Prabhakaran VC, Prakash DR, Chakraborty S (2007) Identification of genes associated with tumorigenesis of meibomian cell carcinoma by microarray analysis. Genomics 90, 559-66.
Ohbayashi N, Okada K, Kawakami S, Togi S, Sato N, Ikeda O, Kamitani S, Muromoto R, Sekine Y, Kawai T, Akira S, Matsuda T (2008) Physical and functional interactions between ZIP kinase and UbcH5. Biochem Biophys Res Commun 372, 708-12.
Xia ZP, Sun L, Chen X, Pineda G, Jiang X, Adhikari A, Zeng W, Chen ZJ (2009) Direct activation of protein kinases by unanchored polyubiquitin chains. Nature 461, 114-9.