From the Evasion of Degradation to Ubiquitin-Dependent Protein Stabilization

Abstract

A hallmark of cancer is dysregulated protein turnover (proteostasis), which involves pathologic ubiquitin-dependent degradation of tumor suppressor proteins, as well as increased oncoprotein stabilization. The latter is due, in part, to mutation within sequences, termed degrons, which are required for oncoprotein recognition by the substrate-recognition enzyme, E3 ubiquitin ligase. Stabilization may also result from the inactivation of the enzymatic machinery that mediates the degradation of oncoproteins. Importantly, inactivation in cancer of E3 enzymes that regulates the physiological degradation of oncoproteins, results in tumor cells that accumulate multiple active oncoproteins with prolonged half-lives, leading to the development of “degradation-resistant” cancer cells. In addition, specific sequences may enable ubiquitinated proteins to evade degradation at the 26S proteasome. While the ubiquitin-proteasome pathway was originally discovered as central for protein degradation, in cancer cells a ubiquitin-dependent protein stabilization pathway actively translates transient mitogenic signals into long-lasting protein stabilization and enhances the activity of key oncoproteins. A central enzyme in this pathway is the ubiquitin ligase RNF4. An intimate link connects protein stabilization with tumorigenesis in experimental models as well as in the clinic, suggesting that pharmacological inhibition of protein stabilization has potential for personalized medicine in cancer. In this review, we highlight old observations and recent advances in our knowledge regarding protein stabilization.

Killing by Degradation: Regulation of Apoptosis by the Ubiquitin-Proteasome-System

“…Cancer cells evade apoptosis by disrupting these checkpoints [ 30 , 31 , 32 ]. The ubiquitin proteasome system (UPS) plays a critical role in keeping this fine-tuned process in check by tightly regulating the levels of anti- and pro-apoptotic proteins [ 19 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ].…”

UBE2B promotes ovarian cancer growth via promoting RAD18 mediated ZMYM2 monoubiquitination and stabilization

“…Ubiquitination is an important post-transcriptional modification of proteins for degradation or stabilization, depending on the type of ubiquitin chain formed [ 1 ]. Ubiquitin has 76 amino-acid residues with seven internal lysine residues (K6, K11, K27, K29, K33, K48, K63) [ 1 ].…”

“…Ubiquitination is an important post-transcriptional modification of proteins for degradation or stabilization, depending on the type of ubiquitin chain formed [ 1 ]. Ubiquitin has 76 amino-acid residues with seven internal lysine residues (K6, K11, K27, K29, K33, K48, K63) [ 1 ]. Proteins can be modified by monoubiquitin or polyubiquitination (via covalent linking of additional ubiquitin molecules) on these lysine residues [ 1 , 2 ].…”

“…Ubiquitin has 76 amino-acid residues with seven internal lysine residues (K6, K11, K27, K29, K33, K48, K63) [ 1 ]. Proteins can be modified by monoubiquitin or polyubiquitination (via covalent linking of additional ubiquitin molecules) on these lysine residues [ 1 , 2 ]. The number of ubiquitin and linkage types have distinct physiological properties.…”

Tumor Progression Locus 2 Protects against Acute Respiratory Distress Syndrome in Influenza A Virus-Infected Mice

“…Tpl2 has previously been studied for its activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), Jun N-terminal protein kinase (JNK), and p38 in response to diverse Toll-like receptors (TLRs), cytokine receptors, G protein-coupled receptors, and Fc receptors ( 48 ). Tpl2 is constitutively associated with NF-κB p105 and A20-binding inhibitor of NF-κB 2 (ABIN-2) ( 49 , 50 ), and following agonist stimulation, the inhibitor of kappa B kinase (IKK) complex phosphorylates NF-κB p105, triggering its K48-linked ubiquitination and proteosomal degradation ( 51 ). Tpl2 release from NF-κB p105 inhibition, coupled with its phosphorylation on serine 400 by IKK2 ( 52 ), enables Tpl2-dependent expression of various pro- and anti-inflammatory mediators.…”