Ubiquitin-proteasome

Emerging evidence suggests that dysfunction of the ubiquitin-proteasome system may be part of the pathophysiology of sporadic Parkinson s disease, especially... 

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

Transforming Growth Factor-Beta Ubiquitin/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 is a highly conserved 8.5 kDa polypeptide, which was first described in 1974. The discovery that the Ubiquitin proteasome system serves as a general mechanism to target proteins for destruction by the proteasome was awarded with the Nobel Prize for Chemistry in 2004. 

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. 

In concordance with the central role of ubiquitin modification in multiple cellular functions perturbations of this system are associated with a variety of diseases. Defects in the control of cell cycle regulators by the ubiquitin proteasome system are connected to cancer progression and many E3 ligases were originally identified as oncogenes. 

As the ubiquitin proteasome pathway is a main route for protein clearance it is not surprising that in protein-opathies (disease caused by aggregate prone proteins) like sporadic Parkinson- or Huntington disease proteasome activity is reduced. Autosomal recessive loss of function of the E3 ligase parkin is the molecular base for one of the most common forms of familial Parkinson disease. 

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. 

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... 

The following also points to a dysregulation of the ubiquitin-proteasome pathway as an important aspect of PD pathogenesis rare mutations in ubiquitin car-boxy-terminal hydrogenase LI (UCH-L1) associated with autosomal dominant PD in a German family [120], a UCH-L1 polymorphism associated with the develop-... 

At least three distinct forms of the IP3-R have been identified, and these share an overall amino acid homology of 60-80%. Type I predominates in the cerebellum and has been most extensively studied. It is the largest of the 3 forms of the receptor and, unlike type II and III receptors, the gene possesses a 120 nucleotide insert. Type II IP3-Rs are found mainly in non-neural tissues, whereas type III receptors occur in both neural and non-neural tissues. In response to chronic activation, IP3-Rs are degraded via the ubiquitin-proteasome pathway [14] (see also Ch. 2). 

McNaught, K. S., Olanow, C. W., Halliwell, B. et al. Failure of the ubiquitin-proteasome system in Parkinson s disease. Nature Reviews, Neuroscience 2 589-594, 2001. 

Oren, M., Schwartz, A. L. and Ciechanover, A. Degradation of the E7 human papillomavirus oncoprotein by the ubiquitin-proteasome system ... 

Aviel, S., Winbeeg, G., Massucci, M. and CiECHANOVEE, A. Degradation of the Epstein-Barr virus latent membrane protein 1 (LMPl) by the ubiquitin-proteasome pathway targeting via ubiquitination of the N-terminal residue. J. Biol Chcm.,... 

A. L. Ubiquitin-proteasome-mediated degradation of Idl is modulated by MyoD. J. Biol. Chem., 2004, 279, 32614-32619. 

Glickman, M. H. and A. Ciechanovee, The ubiquitin-proteasome proteolytic pathway destruction for the sake of construction. Physiol Rev, 2002, 82(2), 373—... 

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