scholarly journals Ligand-dependent Degradation of Smad3 by a Ubiquitin Ligase Complex of ROC1 and Associated Proteins

2001 ◽  
Vol 12 (5) ◽  
pp. 1431-1443 ◽  
Author(s):  
Minoru Fukuchi ◽  
Takeshi Imamura ◽  
Tomoki Chiba ◽  
Takanori Ebisawa ◽  
Masahiro Kawabata ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Ring Finger ◽  
Transforming Growth Factor Β ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Smads are signal mediators for the members of the transforming growth factor-β (TGF-β) superfamily. Upon phosphorylation by the TGF-β receptors, Smad3 translocates into the nucleus, recruits transcriptional coactivators and corepressors, and regulates transcription of target genes. Here, we show that Smad3 activated by TGF-β is degraded by the ubiquitin–proteasome pathway. Smad3 interacts with a RING finger protein, ROC1, through its C-terminal MH2 domain in a ligand-dependent manner. An E3 ubiquitin ligase complex ROC1-SCFFbw1a consisting of ROC1, Skp1, Cullin1, and Fbw1a (also termed βTrCP1) induces ubiquitination of Smad3. Recruitment of a transcriptional coactivator, p300, to nuclear Smad3 facilitates the interaction with the E3 ligase complex and triggers the degradation process of Smad3. Smad3 bound to ROC1-SCFFbw1a is then exported from the nucleus to the cytoplasm for proteasomal degradation. TGF-β/Smad3 signaling is thus irreversibly terminated by the ubiquitin–proteasome pathway.

scholarly journals Transferable Domain in the G1 Cyclin Cln2 Sufficient To Switch Degradation of Sic1 from the E3 Ubiquitin Ligase SCFCdc4 to SCFGrr1

2002 ◽  
Vol 22 (13) ◽  
pp. 4463-4476 ◽  
Author(s):  
Catherine Berset ◽  
Peter Griac ◽  
Rebecca Tempel ◽  
Janna La Rue ◽  
Curt Wittenberg ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Kinase Inhibitor ◽  
E3 Ubiquitin Ligase ◽  
Phosphorylation Sites ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
F Box Protein

ABSTRACT Degradation of Saccharomyces cerevisiae G1 cyclins Cln1 and Cln2 is mediated by the ubiquitin-proteasome pathway and involves the SCF E3 ubiquitin-ligase complex containing the F-box protein Grr1 (SCFGrr1). Here we identify the domain of Cln2 that confers instability and describe the signals in Cln2 that result in binding to Grr1 and rapid degradation. We demonstrate that mutants of Cln2 that lack a cluster of four Cdc28 consensus phosphorylation sites are highly stabilized and fail to interact with Grr1 in vivo. Since one of the phosphorylation sites lies within the Cln2 PEST motif, a sequence rich in proline, aspartate or glutamate, serine, and threonine residues found in many unstable proteins, we fused various Cln2 C-terminal domains containing combinations of the PEST and the phosphoacceptor motifs to stable reporter proteins. We show that fusion of the Cln2 domain to a stabilized form of the cyclin-dependent kinase inhibitor Sic1 (ΔN-Sic1), a substrate of SCFCdc4, results in degradation in a phosphorylation-dependent manner. Fusion of Cln2 degradation domains to ΔN-Sic1 switches degradation of Sic1 from SCFCdc4 to SCFGrr1. ΔN-Sic1 fused with a Cln2 domain containing the PEST motif and four phosphorylation sites binds to Grr1 and is unstable and ubiquitinated in vivo. Interestingly, the phosphoacceptor domain of Cln2 binds to Grr1 but is not ubiquitinated and is stable. In summary, we have identified a small transferable domain in Cln2 that can redirect a stabilized SCFCdc4 target for SCFGrr1-mediated degradation by the ubiquitin-proteasome pathway.

scholarly journals E6-associated protein (E6-AP) is a dual function coactivator of steroid hormone receptors

2008 ◽  
Vol 6 (1) ◽  
pp. nrs.06006 ◽  
Author(s):  
Sivapriya Ramamoorthy ◽  
Zafar Nawaz
Keyword(s):  
Hormone Receptors ◽  
Target Genes ◽  
Steroid Hormone ◽  
Enzymatic Activities ◽  
Steroid Hormone Receptors ◽  
Dual Function ◽  
Biological Functions ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Steroid hormone receptors (SHR) belong to a large family of ligand-activated transcription factors that perform their biological functions by enhancing the transcription of specific target genes. The transactivation functions of SHRs are regulated by a specialized group of proteins called coactivators. The SHR coactivators represent a growing class of proteins with various enzymatic activities that serve to modify the chromatin to facilitate the transcription of SHR target genes. The ubiquitin-proteasome pathway enzymes have also been added to the growing list of enzymatic activities that are recruited to the SHR target gene promoters during transcription. One such ubiquitin-proteasome pathway enzyme to be identified and characterized as a SHR coactivator was E6-associated protein (E6-AP). E6-AP is a hect (homologous to E6-associated protein carboxy-terminal domain) domain containing E3 ubiquitin ligase that possesses two independent separable functions; a coactivation function and an ubiquitin-protein ligase activity. Being a component of the ubiquitin-proteasome pathway, it is postulated that E6-AP may orchestrate the dynamics of steroid hormone receptor-mediated transcription by regulating the degradation of the transcriptional complexes. E6-AP has also been shown to be involved in the regulation of various aspects of reproduction such as prostate and mammary gland development. Furthermore, it has been demonstrated that E6-AP expression is down-regulated in breast and prostate tumors and that the expression of E6-AP is inversely associated with that of estrogen and androgen receptors. This review summarizes our current knowledge about the structures, molecular mechanisms, spatiotemporal expression patterns and biological functions of E6-AP.

scholarly journals Ubiquitin-dependent Degradation of p73 Is Inhibited by PML

2004 ◽  
Vol 199 (11) ◽  
pp. 1545-1557 ◽  
Author(s):  
Francesca Bernassola ◽  
Paolo Salomoni ◽  
Andrew Oberst ◽  
Charles J. Di Como ◽  
Michele Pagano ◽  
...  
Keyword(s):  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Primary Cells ◽  
Tumor Suppressor P53 ◽  
Ubiquitin Proteasome Pathway ◽  
Mitogen Activated Protein ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

p73 has been identified recently as a structural and functional homologue of the tumor suppressor p53. Here, we report that p73 stability is directly regulated by the ubiquitin–proteasome pathway. Furthermore, we show that the promyelocytic leukemia (PML) protein modulates p73 half-life by inhibiting its degradation in a PML–nuclear body (NB)–dependent manner. p38 mitogen-activated protein kinase–mediated phosphorylation of p73 is required for p73 recruitment into the PML-NB and subsequent PML-dependent p73 stabilization. We find that p300-mediated acetylation of p73 protects it against ubiquitinylation and that PML regulates p73 stability by positively modulating its acetylation levels. As a result, PML potentiates p73 transcriptional and proapoptotic activities that are markedly impaired in Pml−/− primary cells. Our findings demonstrate that PML plays a crucial role in modulating p73 function, thus providing further insights on the molecular network for tumor suppression.

scholarly journals Cks1 is degraded via the ubiquitin-proteasome pathway in a cell cycle-dependent manner

2003 ◽  
Vol 8 (11) ◽  
pp. 889-896 ◽  
Author(s):  
Takayuki Hattori ◽  
Kyoko Kitagawa ◽  
Chiharu Uchida ◽  
Toshiaki Oda ◽  
Masatoshi Kitagawa
Keyword(s):  
Cell Cycle ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Proteasome Pathway ◽  
Cycle Dependent

TGF-β induces degradation of TAL1/SCL by the ubiquitin-proteasome pathway through AKT-mediated phosphorylation

Blood ◽  
2009 ◽  
Vol 113 (26) ◽  
pp. 6695-6698 ◽  
Author(s):  
Jean-Michel Terme ◽  
Ludovic Lhermitte ◽  
Vahid Asnafi ◽  
Pierre Jalinot
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Transforming Growth Factor ◽  
Lymphoblastic Leukemia ◽  
Transforming Growth Factor Β ◽  
Leukemic Cells ◽  
Phosphatidylinositol 3 Kinase ◽  
Ubiquitin Proteasome ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Proteasome Pathway

Abstract T-cell acute lymphoblastic leukemia 1 (TAL1), also known as stem cell leukemia (SCL), plays important roles in differentiation of hematopoietic and endothelial cells and is deregulated in a high percentage of T-cell acute lymphoblastic leukemia (T-ALL). In this report we show that the intracellular concentration of TAL1 is regulated by transforming growth factor β (TGF-β), which triggers its polyubiquitylation and degradation by the proteasome. This effect is mediated by AKT1, which phosphorylates TAL1 at threonine 90. Immunoprecipitation experiments showed that this event increases association of TAL1 with the E3 ubiquitin ligase CHIP. The E47 heterodimerization partner of TAL1 hinders this association. Our observations indicate that activation of the TGF-β and phosphatidylinositol 3-kinase/AKT pathways might reverse overexpression of TAL1 in leukemic cells by inducing proteolysis of this important oncogene.

scholarly journals RNF170 Protein, an Endoplasmic Reticulum Membrane Ubiquitin Ligase, Mediates Inositol 1,4,5-Trisphosphate Receptor Ubiquitination and Degradation

2011 ◽  
Vol 286 (27) ◽  
pp. 24426-24433 ◽  
Author(s):  
Justine P. Lu ◽  
Yuan Wang ◽  
Danielle A. Sliter ◽  
Margaret M. P. Pearce ◽  
Richard J. H. Wojcikiewicz
Keyword(s):  
Endoplasmic Reticulum ◽  
Ubiquitin Ligase ◽  
Endoplasmic Reticulum Membrane ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Ligase Activity ◽  
Inositol 1,4,5 Trisphosphate ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Membrane Spanning ◽  
Trisphosphate Receptor

Inositol 1,4,5-trisphosphate (IP3) receptors are endoplasmic reticulum membrane calcium channels that, upon activation, are degraded via the ubiquitin-proteasome pathway. While searching for novel mediators of IP3 receptor processing, we discovered that RNF170, an uncharacterized RING domain-containing protein, associates rapidly with activated IP3 receptors. RNF170 is predicted to have three membrane-spanning helices, is localized to the ER membrane, and possesses ubiquitin ligase activity. Depletion of endogenous RNF170 by RNA interference inhibited stimulus-induced IP3 receptor ubiquitination, and degradation and overexpression of a catalytically inactive RNF170 mutant suppressed stimulus-induced IP3 receptor processing. A substantial proportion of RNF170 is constitutively associated with the erlin1/2 (SPFH1/2) complex, which has been shown previously to bind to IP3 receptors immediately after their activation. Depletion of RNF170 did not affect the binding of the erlin1/2 complex to stimulated IP3 receptors, whereas erlin1/2 complex depletion inhibited RNF170 binding. These results suggest a model in which the erlin1/2 complex recruits RNF170 to activated IP3 receptors where it mediates IP3 receptor ubiquitination. Thus, RNF170 plays an essential role in IP3 receptor processing via the ubiquitin-proteasome pathway.

scholarly journals The ZSWIM8 ubiquitin ligase mediates target-directed microRNA degradation

Science ◽  
2020 ◽  
pp. eabc9359
Author(s):  
Charlie Y. Shi ◽  
Elena R. Kingston ◽  
Benjamin Kleaveland ◽  
Daniel H. Lin ◽  
Michael W. Stubna ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Mechanistic Model ◽  
E3 Ubiquitin Ligase ◽  
Gene Repression ◽  
Loss Of Function ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Mirna Degradation ◽  
Ring E3

MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to direct widespread post-transcriptional gene repression. Although association with AGO typically protects miRNAs from nucleases, extensive pairing to some unusual target RNAs can trigger miRNA degradation. Here we found that this target-directed miRNA degradation (TDMD) required the ZSWIM8 Cullin-RING E3 ubiquitin ligase. This and other findings suggested and supported a mechanistic model of TDMD in which target-directed proteolysis of AGO by the ubiquitin–proteasome pathway exposes the miRNA for degradation. Moreover, loss-of-function studies indicated that the ZSWIM8 Cullin-RING ligase accelerates degradation of numerous miRNAs in cells of mammals, flies, and nematodes, thereby specifying the half-lives of most short-lived miRNAs. These results elucidate the mechanism of TDMD and expand its inferred role in shaping miRNA levels in bilaterian animals.

The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner

2000 ◽  
Vol 113 (23) ◽  
pp. 4363-4371 ◽  
Author(s):  
J. Zhao ◽  
T. Tenev ◽  
L.M. Martins ◽  
J. Downward ◽  
N.R. Lemoine
Keyword(s):  
Cell Cycle ◽  
Proteasome Inhibitors ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Apoptosis Protein ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Proteasome Pathway ◽  
Cycle Dependent

Survivin, a human inhibitor of apoptosis protein (IAP), plays an important role in both cell cycle regulation and inhibition of apoptosis. Survivin is expressed in cells during the G(2)/M phase of the cell cycle, followed by rapid decline of both mRNA and protein levels at the G(1) phase. It has been suggested that cell cycle-dependent expression of survivin is regulated at the transcriptional level. In this study we demonstrate involvement of the ubiquitin-proteasome pathway in post-translational regulation of survivin. Survivin is a short-lived protein with a half-life of about 30 minutes and proteasome inhibitors greatly stabilise survivin in vivo. Expression of the survivin gene under the control of the CMV promoter cannot block cell cycle-dependent degradation of the protein. Proteasome inhibitors can block survivin degradation during the G(1) phase and polyubiquitinated derivatives can be detected in vivo. Mutation of critical amino acid residues within the baculovirus IAP repeat (BIR) domain or truncation of the N terminus or the C terminus sensitises survivin to proteasome degradation. Together, these results indicate that the ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner and structural changes greatly destabilise the survivin protein.

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