Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ubiquitin-protein ligases (E3s) of the HECT family share a conserved catalytic region that is homologous to the E6-AP C terminus. The HECT domain defines a large E3 family, but only a handful of these enzymes have been defined with respect to substrate specificity or biological function. We showed previously that the C-terminal domain of one family member, KIAA10, catalyzes the assembly of polyubiquitin chains, whereas the N-terminal domain binds to proteasomes in vitro (You, J., and Pickart, C. M. (2001) J. Biol. Chem. 276, 19871-19878). We show here that KIAA10 also associates with proteasomes within cells but that this association probably involves additional contacts with proteasome subunits other than the one (S2/Rpn1) identified in our previous work. We report that the N-domain of KIAA10 also mediates an association with TIP120B (TATA-binding protein-interacting protein 120B), a putative transcriptional regulator. Biochemical and co-transfection studies revealed that TIP120B, but not the closely related protein TIP120A, is a specific substrate of KIAA10 in vitro and within C2C12 myoblasts but not in Cos-1 cells. KIAA10 and TIP120B are both highly expressed in human skeletal muscle, suggesting that KIAA10 may regulate TIP120B homeostasis specifically in this tissue.
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PMID:Proteolytic targeting of transcriptional regulator TIP120B by a HECT domain E3 ligase. 1269 29

Despite fast protein degradation in muscles, protein concentrations remain constant during differentiation and maintenance of muscle tissues. Myogenin, a basic helix-loop-helix-type myogenic transcription factor, plays a critical role through transcriptional activation in myogenesis as well as muscle maintenance. TBP-interacting protein 120/cullin-associated neddylation-dissociated (TIP120/CAND) is known to bind to cullin and negatively regulate SCF (Skp1-Cullin1-F-box protein) ubiquitin ligase, although its physiological role has not been elucidated. We have identified a muscle-specific isoform of TIP120, named TIP120B/CAND2. In this study, we found that TIP120B is not only induced in association with myogenic differentiation but also actively accelerates the myogenic differentiation of C2C12 cells. Although myogenin is a short lived protein and is degraded by a ubiquitin-proteasome system, TIP120B suppressed its ubiquitination and subsequent degradation of myogenin. TIP120B bound to cullin family proteins, especially Cullin 1 (CUL1), and was associated with SCF complex in cells. It was demonstrated that myogenin was also associated with SCF and that CUL1 small interference RNA treatment inhibited ubiquitination of myogenin and stabilized it. TIP120B was found to break down the SCF-myogenin complex. Consequently suppression of SCF-dependent ubiquitination of myogenin by TIP120B, which leads to stabilization of myogenin, can account for the TIP120B-directed accelerated differentiation of C2C12 cells. TIP120B is proposed to be a novel regulator for myogenesis.
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PMID:TBP-interacting protein 120B (TIP120B)/cullin-associated and neddylation-dissociated 2 (CAND2) inhibits SCF-dependent ubiquitination of myogenin and accelerates myogenic differentiation. 1724