30% of human tumors, characterizing it as a tumor suppressor protein. Increased ubiquitination activity Cervical cancer Oncogenic types of the human papillomavirus (HPV) are known to hijack cellular ubiquitin-proteasome pathway for viral infection and replication. The E6 proteins of HPV will bind to the N-terminus of the cellular E6-AP E3 ubiquitin ligase, redirecting the complex to bind p53, a well-known tumor suppressor gene whose inactivation is found in many types of cancer. Thus, p53 undergoes ubiquitination and proteasome-mediated degradation. Meanwhile, E7, another one of the early-expressed HPV genes, will bind to Rb, also a tumor suppressor gene, mediating its degradation. The loss of p53 and Rb in cells allows limitless cell proliferation to occur. p53 regulation Gene amplification often occur in various tumor cases, including of MDM2, a gene encodes for a RING E3 Ubiquitin ligase responsible for downregulation of p53 activity. MDM2 targets p53 for ubiquitination and proteasomal degradation thus keeping its level appropriate for normal cell condition. Overexpression of MDM2 causes loss of p53 activity and therefore allowing cells to have a limitless replicative potential. p27 Another gene that is a target of gene amplification is SKP2. SKP2 is an F-box protein with a role in substrate recognition for ubiquitination and degradation. SKP2 targets p27Kip-1, an inhibitor of cyclin-dependent kinases (CDKs). CDKs2/4 partner with the cyclins E/D, respectively, forming a family of cell cycle regulators which control cell cycle progression through the G1 phase. Low level of p27Kip-1 protein is often found in various cancers and is due to overactivation of ubiquitin-mediated proteolysis through overexpression of SKP2. Efp Efp, or estrogen-inducible RING-finger protein, is an E3 ubiquitin ligase whose overexpression has been shown to be the major cause of estrogen-independent breast cancer. Efp's substrate is 14-3-3 protein which negatively regulates cell cycle. Evasion of ubiquitination Colorectal cancer The gene associated with colorectal cancer is the adenomatous polyposis coli (APC), which is a classic tumor suppressor gene. APC gene product targets beta-catenin for degradation via ubiquitination at the N-terminus, thus regulating its cellular level. Most colorectal cancer cases are found with mutations in the APC gene. However, in cases where APC gene is not mutated, mutations are found in the N-terminus of beta-catenin which renders it ubiquitination-free and thus increased activity. Glioblastoma As the most aggressive cancer originated in the brain, mutations found in patients with glioblastoma are related to the deletion of a part of the extracellular domain