Proteasomal degradation

On pharmacodynamic grounds, tumor resistance may be caused by such diverse mechanisms as the mutation or redundancy of topo II, the overexpression and preferred nuclear localization of proteasome a-type subunits (leading to a anomalous degradation of topo II), genetic deletion or loss-of-function mutations of p53, overexpression of ROS-detoxifying enzymes, overexpression of Bcl-2 (leading to a diminished cyt c release), etc. However, none of these factors would universally predict the development of anthracycline-resistance in a given tumor or another. 

In addition to protein proteolysis during mitosis, ubiquitin-mediated protein degradation ( ubiquitin/ proteasome) is also required at the G1 to S transition... 

ER-Associated Degradation, when proteins mis-fold in the ER due to mutation or environmental conditions, they are selectively exported to the cytosol for degradation by the proteasome. 

F-adjacent Transcript-10 (FAT 10) is composed of two ubiquitin-like domains and capable to mark conjugated proteins for proteasomal degradation independent of ubiquitin. FAT10 is inducible by IFN-y and TNF and induces apoptosis when over expressed. 

Ubiquitin tags proteins for protein degradation. The ubiquitination requires three different enzymatic activities, a ubiquitin-activating enzyme (El), a ubiquitin-conjugating enzyme (E2 or Ubc) and a ubiquitin ligase (E3). The action of all three enzymes leads to the establishment of a poly-ubiquitin chain on target proteins which are then recognized and proteolyzed by the 26S proteasome. 

Protein modification by the covalent attachment of ubiquitin chains serves as a signal to mark proteins for the degradation by a multicatalytic proteinase complex called the proteasome. Thus the ubiquitin proteasome system (UPS) controls the stability of proteins in a... 

Ubiquitin/Proteasome. Figure 2 Functional consequences of ubiquitin linkage. Substrates (blue bars) are linked via lysine residues (K) to ubiquitin or ubiquitin chains, (a) Attachment of chains connected via Lysines in position 48 of ubiquitin (K48) targets substrates for proteasomal degradation. In contrast modification of one (b) or multiple (c) lysines by a single ubiquitin molecule mediates novel protein interactions or initiates endocytosis. Conjugation of K63-linked polyubiquitin (d) alters protein function and can also serve as a signal for endocytosis. 

The UPS also plays a major role in protein quality control. In a process known as endoplasmic associated degradation (ERAD), misfolded proteins, which are formed in the endoplasmatic reticulum, are translocated back to the cytoplasm and degraded by the proteasome. 

Proteasomal degradation also plays an essential role in the activation of cellular signaling pathways. A prototype for this is the control of NF-kB signaling, which has a pivotal role in inflammatory responses. Upon stimulation the inhibitory IicBa protein is phos-phorylated and thereby becomes a target substrate for K48-polyubiquitination. Proteasomal degradation of IkBu releases the transcription factor NF-kB, which subsequently translocates to the nucleus and activates specific target genes. 

In Cystic fibrosis a point mutation of the cystic fibrosis transmembrane regulator (CTFR) prevents transport of this molecule to the cell surface. Instead this otherwise functional molecule is degraded by the ERAD-ubiquitin proteasome pathway. 

There is considerable evidence that a second trans-poson in the ER membrane is involved in retrograde transport of various molecules from the ER lumen to the cytosol. These molecules include unfolded or mis-folded glycoproteins, glycopeptides, and oligosaccharides. Some at least of these molecules are degraded in proteasomes. Thus, there is two-way traffic across the ER membrane. 

Mehle A, Strack B, Ancuta P, Zhang C, McPike M, Gabuzda D (2004) Vif overcomes the innate antiviral activity of APOBEC3G by promoting its degradation in the ubiquitin-proteasome pathway. J Biol Chem 279(9) 7792-7798... 

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