Negative regulation of SCFSkp2 ubiquitin ligase by TGF-β signaling

Wang, Wei; Ungermannova, Dana; Jin, Jianpin; Harper, J. Wade; Liu, Xuedong

doi:10.1038/sj.onc.1207204

Cited by 44 publications

(42 citation statements)

References 58 publications

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“…We show that Skp2 levels are regulated by Cks1. Our cellbased assays complement previous in vitro studies which indicate that Cks1 may stabilize Skp2 protein by preventing its ubiquitylation and subsequent proteasomal degradation (Wang et al, 2004). Notably, Skp2 mRNA levels in melanoma cells are not altered by cyclin D1 knockdown (Figure 6a) or by Cks1 knockdown (data not shown).…”

Section: Discussionsupporting

confidence: 86%

“…Thus, our data indicate that mutant B-RAF and cyclin D1 control expression of Cks1, which in turn stabilizes Skp2 levels. Regulation of Skp2 through this pathway likely occurs through inhibiting Skp2 ubiquitylation, and may involve the anaphasepromoting complex/cyclosome-Cdh1 complex that is known to degrade Skp2 (Bashir et al, 2004;Wang et al, 2004;Wei et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Figure 6a); hence, we investigated the role of Cks1, a cofactor for Skp2 that prevents Skp2 auto-ubiquitylation and degradation (Ganoth et al, 2001;Spruck et al, 2001;Wang et al, 2004). Expression of Cks1 was higher in WM793 and WM115 cells compared to NHEM (Figure 6b).…”

Section: Skp2 Is Required For Downregulation Of P27 Kip1 Levels In Mementioning

confidence: 97%

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Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells

Bhatt

Spofford

et al. 2006

Oncogene

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells

Bhatt

Spofford

et al. 2006

Oncogene

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“…Kip1 (25). In contrast to epithelial cells, TGF-␤ promotes chondrocyte proliferation through activation of cyclin D 1 (Refs.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β Stimulates Cyclin D1 Expression through Activation of β-Catenin Signaling in Chondrocytes

Li¹,

Chen²,

et al. 2006

Journal of Biological Chemistry

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Transforming growth factor-␤ (TGF-␤) plays an essential role in chondrocyte maturation. It stimulates chondrocyte proliferation but inhibits chondrocyte differentiation. In this study, we found that TGF-␤ rapidly induced ␤-catenin protein levels and signaling in murine neonatal sternal primary chondrocytes. TGF-␤-increased ␤-catenin induction was reproduced by overexpression of SMAD3 and was absent in Smad3 ؊/؊ chondrocytes treated with TGF-␤. SMAD3 inhibited ␤-transducin repeat-containing protein-mediated degradation of ␤-catenin and immunoprecipitated with ␤-catenin following TGF-␤ treatment. Both SMAD3 and ␤-catenin co-localized to the nucleus after TGF-␤ treatment. Although both TGF-␤ and ␤-catenin stimulated cyclin D 1 expression in chondrocytes, the effect of TGF-␤ was inhibited with ␤-catenin gene deletion or SMAD3 loss of function. These results demonstrate that TGF-␤ stimulates cyclin D 1 expression at least in part through activation of ␤-catenin signaling.Endochondral bone formation involves condensation and differentiation of mesenchymal cells into chondrocytes, followed by chondrocyte proliferation, maturation, hypertrophic differentiation, and apoptosis. Eventually, the calcified cartilage tissue formed in the growth plate is replaced by bone tissue (1). Each step of the endochondral bone formation process is precisely regulated by local growth factors. Among these factors, transforming growth factor-␤ (TGF-␤) 3 plays important roles in chondrocyte proliferation and hypertrophy. TGF-␤ promotes chondrocyte proliferation but inhibits chondrocyte differentiation and hypertrophy (2-6). The mechanism of TGF-␤-induced chondrocyte proliferation remains undefined.In this study, we investigated the interaction between TGF-␤ and ␤-catenin signaling in chondrocytes. We found that TGF-␤ activates ␤-catenin signaling through SMAD3. SMAD3 interacted with ␤-catenin and increased ␤-catenin nuclear translocation and signaling. Although TGF-␤ stimulated cyclin D 1 expression in chondrocytes, this effect was abolished by inhibition of ␤-catenin signaling. These results demonstrate for the first time that TGF-␤ stimulates cyclin D 1 expression in chondrocytes at least in part through activation of ␤-catenin signaling. These findings provide novel insight regarding the mechanism through which TGF-␤ regulates chondrocyte proliferation. MATERIALS AND METHODS Cell Culture-Smad3Ϫ/Ϫ mice derived from a C57/B6 lineage, in which exon 8 of the Smad3 gene is deleted (a kind gift from Dr. C. X. Deng, National Institutes of Health, Bethesda, MD) (7), were bred using heterozygote pairs. 3-day-old neonatal mice were killed and genotyped using tail tissues obtained at the time of death. The anterior rib cage and sternum were harvested en bloc, washed with sterile phosphate-buffered saline (PBS), and then digested with Pronase (Roche Applied Science) dissolved in PBS (2 mg/ml) in a 37°C water bath with continuous shaking for 60 min. This was followed by incubation in a solution of collagenase D (3 mg/ml dissolved in serum-free Dulbec...

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“…This finding suggests that their degradation is mediated via an 'autocatalytic' mechanism (mediated by the RING finger components). [34][35][36][37] Interestingly, it was observed that the degradation of several F-box proteins is attenuated by their respective substrates. 16,34,36 It was recently uncovered that a WD40 repeat, which is present in a large subset of substrate receptors, can bind ubiquitin.…”

Section: Degradation Of Ligases Via Self-catalyzed Ubiquitinationmentioning

confidence: 99%

Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms

2011

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Ubiquitin modification of many cellular proteins targets them for proteasomal degradation, but in addition can also serve non-proteolytic functions. Over the last years, a significant progress has been made in our understanding of how modification of the substrates of the ubiquitin system is regulated. However, little is known on how the ubiquitin system that is comprised of B1500 components is regulated. Here, we discuss how the biggest subfamily within the system, that of the E3 ubiquitin ligases that endow the system with its high specificity towards the numerous substrates, is regulated and in particular via self-regulation mediated by ubiquitin modification. Ligases can be targeted for degradation in a self-catalyzed manner, or through modification mediated by an external ligase(s). In addition, non-proteolytic functions of self-ubiquitination, for example activation of the ligase, of E3s are discussed. Cell Death and Differentiation (2011) 18, 1393-1402 doi:10.1038/cdd.2011; published online 4 March 2011One of the major roles of the covalent modification of cellular proteins by ubiquitin is signaling them for proteasomal degradation ( Figure 1). The first step of the modification is catalyzed by the ubiquitin-activating enzyme, E1, which generates a high-energy thiol ester intermediate that is subsequently transferred to the second enzyme, a ubiquitinconjugating enzyme, E2. The third step ascertains substrate specificity, and is catalyzed by one of the numerous (B650) ubiquitin ligases, E3s. Typically, it results in the formation of an isopeptide bond between the C-terminal Gly of ubiquitin and an e-NH 2 group of an internal Lys of the substrate. Less frequently, it can generate a linear peptide bond with the a-NH 2 group, a thiol ester bond with an internal Cys, or an ester bond with a Thr or Ser. The three-step cascade of reactions is repeated, where additional ubiquitin moieties are attached sequentially to one another in an isopeptide bond involving one of the seven internal Lys residues in the ubiquitin moiety, thus generating a polyubiquitin chain. Lys48-based chains serve as a signal for proteasomal degradation, whereas chains based on other internal Lys residues, or modification by single moiety(ies) can serve non-proteolytic functions.Ligases fall into two main families: RING (really interesting new gene) and HECT (homologous to the E6-AP carboxy terminus) domain-containing E3s. RING ligases serve as scaffolds that facilitate direct transfer of ubiquitin from the E2 to the target protein. HECT E3s contain an active Cys residue to which ubiquitin binds prior to its transfer to the substrate (Figure 1). There are B600 RING finger and B30 HECT ligases in humans. Smaller families of ligases (U-box, plant homology domain, and zinc finger) have also been described.An important problem relates to regulation of the ubiquitin system components, and in particular to that of the ligases that are the specific substrate-recognizing elements. 1,2 Phosphorylation of an E3 can activate the protein, such as the ca...

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Negative regulation of SCFSkp2 ubiquitin ligase by TGF-β signaling

Cited by 44 publications

References 58 publications

Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells

Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells

Transforming Growth Factor-β Stimulates Cyclin D1 Expression through Activation of β-Catenin Signaling in Chondrocytes

Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms

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