Ubiquitin Ligase

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Hui Zhang - One of the best experts on this subject based on the ideXlab platform.

Michele Pagano - One of the best experts on this subject based on the ideXlab platform.

  • SCF Ubiquitin Ligase targeted therapies
    Nature reviews. Drug discovery, 2014
    Co-Authors: Jeffrey R. Skaar, Julia K. Pagan, Michele Pagano
    Abstract:

    The clinical successes of proteasome inhibitors for the treatment of cancer have highlighted the therapeutic potential of targeting this protein degradation system. However, proteasome inhibitors prevent the degradation of numerous proteins, which may cause adverse effects. Increased specificity could be achieved by inhibiting the components of the Ubiquitin-proteasome system that target specific subsets of proteins for degradation. F-box proteins are the substrate-targeting subunits of SKP1-CUL1-F-box protein (SCF) Ubiquitin Ligase complexes. Through the degradation of a plethora of diverse substrates, SCF Ubiquitin Ligases control a multitude of processes at the cellular and organismal levels, and their dysregulation is implicated in many pathologies. SCF Ubiquitin Ligases are characterized by their high specificity for substrates, and these Ligases therefore represent promising drug targets. However, the potential for therapeutic manipulation of SCF complexes remains an underdeveloped area. This Review explores and discusses potential strategies to target SCF-mediated biological processes to treat human diseases.

  • PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 Ubiquitin Ligase complex
    Genes and Development, 2008
    Co-Authors: Tarek Abbas, Virginia Amador, Kenta Terai, U Sivaprasad, Michele Pagano, Anindya Dutta
    Abstract:

    The DNA polymerase delta processivity factor Proliferating Cell Nuclear Antigen (PCNA) promotes the DNA damage-induced degradation of the replication initiation factor Cdt1 via the CRL4(Cdt2) E3 Ubiquitin Ligase complex. Here we demonstrate that PCNA promotes the ubiquitylation and degradation of the CDK inhibitor p21 in cells irradiated with low dose of ultraviolet (UV) by a similar mechanism. Human cells that are depleted of Cul4, DDB1 (damage-specific DNA-binding protein-1), or the DCAF Cdt2, are deficient in the UV-induced ubiquitylation and degradation of p21. Depletion of mammalian cells of PCNA by siRNA, or mutations in p21 that abrogate PCNA binding, prevent UV-induced p21 ubiquitylation and degradation, indicating that physical binding with PCNA is necessary for the efficient ubiquitylation of p21 via the CRL4(Cdt2) Ubiquitin Ligase. Cdt2 functions as the substrate recruiting factor for p21 to the rest of the CRL4 Ubiquitin Ligase complex. The CRL4(Cdt2) E3 Ubiquitin Ligase ubiquitylates p21 both in vivo and in vitro, and its activity is dependent on the interaction of p21 with PCNA. Finally, we show that the CRL4(Cdt2) and the SCF(Skp2) Ubiquitin Ligases are redundant with each other in promoting the degradation of p21 during an unperturbed S phase of the cell cycle.

  • The SCF Ubiquitin Ligase: insights into a molecular machine
    Nature Reviews Molecular Cell Biology, 2004
    Co-Authors: Timothy Cardozo, Michele Pagano
    Abstract:

    Ubiquitin Ligases are well suited to regulate molecular networks that operate on a post-translational timescale. The F-box family of proteins — which are the substrate-recognition components of the Skp1–Cul1–F-box-protein (SCF) Ubiquitin Ligase — are important players in many mammalian functions. Here we explore a unifying and structurally detailed view of SCF-mediated proteolytic control of cellular processes that has been revealed by recent studies. The SCF complex is a multi-subunit Ubiquitin Ligase that specifically transfers activated Ubiquitin to target-protein substrates. SCF is named after Skp1–Cullin–F-box-protein, which are the three main proteins of the complex. A RING-domain-containing protein of the Roc1/Rbx1 family is the final component of the Ligase. The F-box-protein (FBP) component of SCF is the element that specifically binds to substrates. The FBP is therefore the main specificity determinant of the SCF, and a wide variety of cellular and developmental processes have been attributed to FBP function. The post-translational nature of Ubiquitin-mediated proteolytic degradation indicates that Ubiquitin Ligases such as SCF are well suited to regulate multi-component molecular machines like the DNA-synthesis and mitotic machinery, and transition points like the cell-cycle checkpoints. The regulation of p27, p21, cyclin E, Cdc25a and Wee1 by SCF, along with SCF interregulation with the APC/C Ubiquitin Ligase, can be unified in a view of SCF Ligases that modulate the cell cycle through the degradation of CDK subunits and their regulators. The three-dimensional structure of SCF-component proteins reveals that the SCF might operate through a unique and flexible 'super-enzymatic' mechanism, which might be amenable to therapeutic intervention in diseases of cellular proliferation.

  • the scf Ubiquitin Ligase insights into a molecular machine
    Nature Reviews Molecular Cell Biology, 2004
    Co-Authors: Timothy Cardozo, Michele Pagano
    Abstract:

    Ubiquitin Ligases are well suited to regulate molecular networks that operate on a post-translational timescale. The F-box family of proteins — which are the substrate-recognition components of the Skp1–Cul1–F-box-protein (SCF) Ubiquitin Ligase — are important players in many mammalian functions. Here we explore a unifying and structurally detailed view of SCF-mediated proteolytic control of cellular processes that has been revealed by recent studies.

  • control of the scf skp2 cks1 Ubiquitin Ligase by the apc c cdh1 Ubiquitin Ligase
    Nature, 2004
    Co-Authors: Tarig Bashir, Virginia Amador, Valerio N Dorrello, Daniele Guardavaccaro, Michele Pagano
    Abstract:

    Skp2 and its cofactor Cks1 are the substrate-targeting subunits of the SCFSkp2–Cks1 (Skp1/Cul1/F-box protein) Ubiquitin Ligase complex that regulates entry into S phase by inducing the degradation of the cyclin-dependent kinase inhibitors p21 and p27 (ref. 1). Skp2 is an oncoprotein that often shows increased expression in human cancers2; however, the mechanism that regulates its cellular abundance is not well understood. Here we show that both Skp2 and Cks1 proteins are unstable in G1 and that their degradation is mediated by the Ubiquitin Ligase APC/CCdh1 (anaphase-promoting complex/cyclosome and its activator Cdh1). Silencing of Cdh1 by RNA interference in G1 cells stabilizes Skp2 and Cks1, with a consequent increase in p21 and p27 proteolysis. Depletion of Cdh1 also increases the percentage of cells in S phase, whereas concomitant downregulation of Skp2 reverses this effect, showing that Skp2 is an essential target of APC/CCdh1. Expression of a stable Skp2 mutant that cannot bind APC/CCdh1 induces premature entry into S phase. Thus, the induction of Skp2 and Cks1 degradation in G1 represents a principal mechanism by which APC/CCdh1 prevents the unscheduled degradation of SCFSkp2–Cks1 substrates and maintains the G1 state.

Leigh Ann Higa - One of the best experts on this subject based on the ideXlab platform.

Hideyo Yasuda - One of the best experts on this subject based on the ideXlab platform.

  • Activity of MDM2, a Ubiquitin Ligase, toward p53 or itself is dependent on the RING finger domain of the Ligase
    Oncogene, 2000
    Co-Authors: R Honda, Hideyo Yasuda
    Abstract:

    We previously showed that oncoprotein MDM2 has Ubiquitin Ligase activity toward tumor suppressor p53. In that paper, we showed very weak homology in the carboxyl terminal portion between MDM2 and E6AP (HECT domain). We mutated the cysteine residue (C464) corresponding to the residue essential for the Ubiquitin Ligase activity of E6AP and this mutation diminished the Ligase activity of MDM2. The cysteine residue described above is also one of the cysteine residues that form the RING finger domain of MDM2. We tried to find out whether the diminishing of the activity by the mutation is attributable to the disruption of the RING finger domain or not. When the ring finger domain of MDM2 was deleted, the truncation mutant did not have the Ubiquitin Ligase activity. When we mutated the seven cysteine residues of RING finger domain of MDM2 in the carboxyl terminus, the disruption of each residue in the RING finger completely diminished the Ubiquitin Ligase activity of MDM2 toward MDM2 itself and toward tumor suppressor p53. These data indicate that the RING finger domain in MDM2 is essential for its Ubiquitin Ligase activity toward p53 and itself.

  • association of p19arf with mdm2 inhibits Ubiquitin Ligase activity of mdm2 for tumor suppressor p53
    The EMBO Journal, 1999
    Co-Authors: Reiko Honda, Hideyo Yasuda
    Abstract:

    We have demonstrated previously that the oncoprotein Mdm2 has a Ubiquitin Ligase activity for the tumor suppressor p53 protein. In the present study, we characterize this Ubiquitin Ligase activity of Mdm2. We first demonstrate the Ubiquitination of several p53 point mutants and deletion mutants by Mdm2. The point mutants, which cannot bind to Mdm2, are not Ubiquitinated by Mdm2. The Ubiquitination of the C-terminal deletion mutants, which contain so-called Mdm2-binding sites, is markedly decreased, compared with that of wild-type p53. The binding of Mdm2 to p53 is essential for Ubiquitination, but p53's tertiary structure and/or C-terminal region may also be important for this reaction. DNA-dependent protein kinase is known to phosphorylate p53 on Mdm2-binding sites, where DNA damage induces phosphorylation, and p53 phosphorylated by this kinase is not a good substrate for Mdm2. This suggests that DNA damage-induced phosphorylation stabilizes p53 by inhibiting its Ubiquitination by Mdm2. We further investigated whether the tumor suppressor p19(ARF) affects the Ubiquitin Ligase activity of Mdm2 for p53. The activity of p19(ARF)-bound Mdm2 was found to be lower than that of free Mdm2, suggesting that p19(ARF) promotes the stabilization of p53 by inactivating Mdm2.

  • oncoprotein mdm2 is a Ubiquitin Ligase e3 for tumor suppressor p53
    FEBS Letters, 1997
    Co-Authors: Reiko Honda, Hirofumi Tanaka, Hideyo Yasuda
    Abstract:

    The tumor suppressor p53 is degraded by the Ubiquitin-proteasome system. p53 was polyUbiquitinated in the presence of E1, UbcH5 as E2 and MDM2 oncoprotein. A Ubiquitin molecule bound MDM2 through sulfhydroxy bond which is characteristic of Ubiquitin Ligase (E3)-Ubiquitin binding. The cysteine residue in the carboxyl terminus of MDM2 was essential for the activity. These data suggest that the MDM2 protein, which is induced by p53, functions as a Ubiquitin Ligase, E3, in human papillomavirus-uninfected cells which do not have E6 protein.

Randall T. Moon - One of the best experts on this subject based on the ideXlab platform.

  • The KLHL12–Cullin-3 Ubiquitin Ligase negatively regulates the Wnt–β-catenin pathway by targeting Dishevelled for degradation
    Nature Cell Biology, 2006
    Co-Authors: Stephane Angers, Chris J. Thorpe, Travis L. Biechele, Seth J. Goldenberg, Ning Zheng, Michael J. Maccoss, Randall T. Moon
    Abstract:

    Dishevelled is a conserved protein that interprets signals received by Frizzled receptors. Using a tandem-affinity purification strategy and mass spectrometry we have identified proteins associated with Dishevelled, including a Cullin-3 Ubiquitin Ligase complex containing the Broad Complex , Tramtrack and Bric à Brac (BTB) protein Kelch-like 12 (KLHL12). This E3 Ubiquitin Ligase complex is recruited to Dishevelled in a Wnt-dependent manner that promotes its poly-Ubiquitination and degradation. Functional analyses demonstrate that regulation of Dishevelled by this Ubiquitin Ligase antagonizes the Wnt–ß-catenin pathway in cultured cells, as well as in Xenopus and zebrafish embryos. Considered with evidence that the distinct Cullin-1 based SCF^β-TrCPcomplex regulates β-catenin stability, our data on the stability of Dishevelled demonstrates that two distinct Ubiquitin Ligase complexes regulate the Wnt–ß-catenin pathway.

  • the klhl12 cullin 3 Ubiquitin Ligase negatively regulates the wnt β catenin pathway by targeting dishevelled for degradation
    Nature Cell Biology, 2006
    Co-Authors: Stephane Angers, Chris J. Thorpe, Travis L. Biechele, Seth J. Goldenberg, Ning Zheng, Michael J. Maccoss, Randall T. Moon
    Abstract:

    Dishevelled is a conserved protein that interprets signals received by Frizzled receptors. Using a tandem-affinity purification strategy and mass spectrometry we have identified proteins associated with Dishevelled, including a Cullin-3 Ubiquitin Ligase complex containing the Broad Complex, Tramtrack and Bric a Brac (BTB) protein Kelch-like 12 (KLHL12). This E3 Ubiquitin Ligase complex is recruited to Dishevelled in a Wnt-dependent manner that promotes its poly-Ubiquitination and degradation. Functional analyses demonstrate that regulation of Dishevelled by this Ubiquitin Ligase antagonizes the Wnt-beta-catenin pathway in cultured cells, as well as in Xenopus and zebrafish embryos. Considered with evidence that the distinct Cullin-1 based SCF(beta-TrCP)complex regulates beta-catenin stability, our data on the stability of Dishevelled demonstrates that two distinct Ubiquitin Ligase complexes regulate the Wnt-beta-catenin pathway.

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