Ubiquitination, or ubiquitin conjugation to proteins, is a crucial process for cell cycle progression and cell proliferation and development. Although ubiquitination usually serves as a signal for protein degradation through the 26S proteasome, it could also serve for other fundamental cellular processes, e.g. in endocytosis, enzymatic activation and DNA repair. Moreover, since ubiquitination functions to tightly regulate the cellular level of cyclins, its misregulation is expected to have severe impacts. First evidence of the importance of the ubiquitin/proteasome pathway in oncogenic processes was observed due to the high antitumor activity of proteasome inhibitors. Various studies have shown that defects or alterations in ubiquitination processes are commonly associated with or present in human carcinoma. Malignancies could be developed through loss of function mutation directly at the tumor suppressor gene, increased activity of ubiquitination, and/or indirect attenuation of ubiquitination due to mutation in related proteins. Direct loss of function mutation of E3 ubiquitin ligase Renal cell carcinoma The VHL (Von Hippel–Lindau) gene encodes a component of an E3 ubiquitin ligase. VHL complex targets a member of the hypoxia-inducible transcription factor family (HIF) for degradation by interacting with the oxygen-dependent destruction domain under normoxic conditions. HIF activates downstream targets such as the vascular endothelial growth factor (VEGF), promoting angiogenesis. Mutations in VHL prevent degradation of HIF and thus lead to the formation of hypervascular lesions and renal tumors. Breast cancer The BRCA1 gene is another tumor suppressor gene in humans which encodes the BRCA1 protein that is involved in response to DNA damage. The protein contains a RING motif with E3 Ubiquitin Ligase activity. BRCA1 could form dimer with other molecules, such as BARD1 and BAP1, for its ubiquitination activity. Mutations that affect the ligase function are often found and associated with various cancers. Cyclin E As processes in cell cycle progression are the most fundamental processes for cellular growth and differentiation, and are the most common to be altered in human carcinomas, it is expected for cell cycle-regulatory proteins to be under tight regulation. The level of cyclins, as the name suggests, is high only at certain a time point during the cell cycle. This is achieved by continuous control of cyclins or CDKs levels through ubiquitination and degradation. When cyclin E is partnered with CDK2 and gets phosphorylated, an SCF-associated F-box protein Fbw7 recognizes the complex and thus targets it for degradation. Mutations in Fbw7 have been found in more than