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Journal articles on the topic 'ROC1'

Author: Grafiati

Published: 4 June 2021

Last updated: 1 February 2022

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1

Donaldson, Timothy D., Maher A. Noureddine, Patrick J. Reynolds, William Bradford, and Robert J. Duronio. "Targeted Disruption of Drosophila Roc1b Reveals Functional Differences in the Roc Subunit of Cullin-dependent E3 Ubiquitin Ligases." Molecular Biology of the Cell 15, no. 11 (November 2004): 4892–903. http://dx.doi.org/10.1091/mbc.e04-03-0180.

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Cullin-dependent ubiquitin ligases regulate a variety of cellular and developmental processes by recruiting specific proteins for ubiquitin-mediated degradation. Cullin proteins form a scaffold for two functional modules: a catalytic module comprised of a small RING domain protein Roc1/Rbx1 and a ubiquitin-conjugating enzyme (E2), and a substrate recruitment module containing one or more proteins that bind to and bring the substrate in proximity to the catalytic module. Here, we present evidence that the three Drosophila Roc proteins are not functionally equivalent. Mutation of Roc1a causes lethality that cannot be rescued by expression of Roc1b or Roc2 by using the Roc1a promoter. Roc1a mutant cells hyperaccumulate Cubitus interruptus, a transcription factor that mediates Hedgehog signaling. This phenotype is not rescued by expression of Roc2 and only partially by expression of Roc1b. Targeted disruption of Roc1b causes male sterility that is partially rescued by expression of Roc1a by using the Roc1b promoter, but not by similar expression of Roc2. These data indicate that Roc proteins play nonredundant roles during development. Coimmunoprecipitation followed by Western or mass spectrometric analysis indicate that the three Roc proteins preferentially bind certain Cullins, providing a possible explanation for the distinct biological activities of each Drosophila Roc/Rbx.

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2

Wu, Kenneth, Serge Y. Fuchs, Angus Chen, Peilin Tan, Carlos Gomez, Ze'ev Ronai, and Zhen-Qiang Pan. "The SCFHOS/β-TRCP-ROC1 E3 Ubiquitin Ligase Utilizes Two Distinct Domains within CUL1 for Substrate Targeting and Ubiquitin Ligation." Molecular and Cellular Biology 20, no. 4 (February 15, 2000): 1382–93. http://dx.doi.org/10.1128/mcb.20.4.1382-1393.2000.

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ABSTRACT We describe a purified ubiquitination system capable of rapidly catalyzing the covalent linkage of polyubiquitin chains onto a model substrate, phosphorylated IκBα. The initial ubiquitin transfer and subsequent polymerization steps of this reaction require the coordinated action of Cdc34 and the SCFHOS/β-TRCP-ROC1 E3 ligase complex, comprised of four subunits (Skp1, cullin 1 [CUL1], HOS/β-TRCP, and ROC1). Deletion analysis reveals that the N terminus of CUL1 is both necessary and sufficient for binding Skp1 but is devoid of ROC1-binding activity and, hence, is inactive in catalyzing ubiquitin ligation. Consistent with this, introduction of the N-terminal CUL1 polypeptide into cells blocks the tumor necrosis factor alpha-induced and SCF-mediated degradation of IκB by forming catalytically inactive complexes lacking ROC1. In contrast, the C terminus of CUL1 alone interacts with ROC1 through a region containing the cullin consensus domain, to form a complex fully active in supporting ubiquitin polymerization. These results suggest the mode of action of SCF-ROC1, where CUL1 serves as a dual-function molecule that recruits an F-box protein for substrate targeting through Skp1 at its N terminus, while the C terminus of CUL1 binds ROC1 to assemble a core ubiquitin ligase.

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3

Maeda, Ichiro, Tomohiko Ohta, Hirotaka Koizumi, and Mamoru Fukuda. "In vitro ubiquitination of cyclin D1 by ROC1-CUL1 and ROC1-CUL3." FEBS Letters 494, no. 3 (April 10, 2001): 181–85. http://dx.doi.org/10.1016/s0014-5793(01)02343-2.

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4

Fukuchi, Minoru, Takeshi Imamura, Tomoki Chiba, Takanori Ebisawa, Masahiro Kawabata, Keiji Tanaka, and Kohei Miyazono. "Ligand-dependent Degradation of Smad3 by a Ubiquitin Ligase Complex of ROC1 and Associated Proteins." Molecular Biology of the Cell 12, no. 5 (May 2001): 1431–43. http://dx.doi.org/10.1091/mbc.12.5.1431.

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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.

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5

Furukawa, Manabu, Yanping Zhang, Joseph McCarville, Tomohiko Ohta, and Yue Xiong. "The CUL1 C-Terminal Sequence and ROC1 Are Required for Efficient Nuclear Accumulation, NEDD8 Modification, and Ubiquitin Ligase Activity of CUL1." Molecular and Cellular Biology 20, no. 21 (November 1, 2000): 8185–97. http://dx.doi.org/10.1128/mcb.20.21.8185-8197.2000.

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ABSTRACT Members of the cullin and RING finger ROC protein families form heterodimeric complexes to constitute a potentially large number of distinct E3 ubiquitin ligases. We report here that the highly conserved C-terminal sequence in CUL1 is dually required, both for nuclear localization and for modification by NEDD8. Disruption of ROC1 binding impaired nuclear accumulation of CUL1 and decreased NEDD8 modification in vivo but had no effect on NEDD8 modification of CUL1 in vitro, suggesting that ROC1 promotes CUL1 nuclear accumulation to facilitate its NEDD8 modification. Disruption of NEDD8 binding had no effect on ROC1 binding, nor did it affect nuclear localization of CUL1, suggesting that nuclear localization and NEDD8 modification of CUL1 are two separable steps, with nuclear import preceding and required for NEDD8 modification. Disrupting NEDD8 modification diminishes the IκBα ubiquitin ligase activity of CUL1. These results identify a pathway for regulation of CUL1 activity—ROC1 and the CUL1 C-terminal sequence collaboratively mediate nuclear accumulation and NEDD8 modification, facilitating assembly of active CUL1 ubiquitin ligase. This pathway may be commonly utilized for the assembly of other cullin ligases.

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6

Furukawa, Manabu, and Yue Xiong. "BTB Protein Keap1 Targets Antioxidant Transcription Factor Nrf2 for Ubiquitination by the Cullin 3-Roc1 Ligase." Molecular and Cellular Biology 25, no. 1 (January 1, 2005): 162–71. http://dx.doi.org/10.1128/mcb.25.1.162-171.2005.

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ABSTRACT The concentrations and functions of many eukaryotic proteins are regulated by the ubiquitin pathway, which consists of ubiquitin activation (E1), conjugation (E2), and ligation (E3). Cullins are a family of evolutionarily conserved proteins that assemble by far the largest family of E3 ligase complexes. Cullins, via a conserved C-terminal domain, bind with the RING finger protein Roc1 to recruit the catalytic function of E2. Via a distinct N-terminal domain, individual cullins bind to a protein motif present in multiple proteins to recruit specific substrates. Cullin 3 (Cul3), but not other cullins, binds directly with BTB domains to constitute a potentially large number of BTB-CUL3-ROC1 E3 ubiquitin ligases. Here we report that the human BTB-Kelch protein Keap1, a negative regulator of the antioxidative transcription factor Nrf2, binds to CUL3 and Nrf2 via its BTB and Kelch domains, respectively. The KEAP1-CUL3-ROC1 complex promoted NRF2 ubiquitination in vitro and knocking down Keap1 or CUL3 by short interfering RNA resulted in NRF2 protein accumulation in vivo. We suggest that Keap1 negatively regulates Nrf2 function in part by targeting Nrf2 for ubiquitination by the CUL3-ROC1 ligase and subsequent degradation by the proteasome. Blocking NRF2 degradation in cells expressing both KEAP1 and NRF2 by either inhibiting the proteasome activity or knocking down Cul3, resulted in NRF2 accumulation in the cytoplasm. These results may reconcile previously observed cytoplasmic sequestration of NRF2 by KEAP1 and suggest a possible regulatory step between KEAP1-NRF2 binding and NRF2 degradation.

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7

Trupkin, Santiago A., Santiago Mora-García, and Jorge J. Casal. "The cyclophilin ROC1 links phytochrome and cryptochrome to brassinosteroid sensitivity." Plant Journal 71, no. 5 (July 6, 2012): 712–23. http://dx.doi.org/10.1111/j.1365-313x.2012.05013.x.

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8

Furukawa, Manabu, Yizhou Joseph He, Christoph Borchers, and Yue Xiong. "Targeting of protein ubiquitination by BTB–Cullin 3–Roc1 ubiquitin ligases." Nature Cell Biology 5, no. 11 (October 5, 2003): 1001–7. http://dx.doi.org/10.1038/ncb1056.

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9

Chen, Angus, Kenneth Wu, Serge Y. Fuchs, Peilin Tan, Carlos Gomez, and Zhen-Qiang Pan. "The Conserved RING-H2 Finger of ROC1 Is Required for Ubiquitin Ligation." Journal of Biological Chemistry 275, no. 20 (March 13, 2000): 15432–39. http://dx.doi.org/10.1074/jbc.m907300199.

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10

Huang, J., and J. Chen. "VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation." Oncogene 27, no. 29 (March 10, 2008): 4056–64. http://dx.doi.org/10.1038/onc.2008.44.

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11

Hu, J., S. Zacharek, Y. J. He, H. Lee, S. Shumway, R. J. Duronio, and Y. Xiong. "WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase." Genes & Development 22, no. 7 (April 1, 2008): 866–71. http://dx.doi.org/10.1101/gad.1624008.

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12

Panasyuk, Ganna, Ivan Nemazanyy, Valeriy Filonenko, and Ivan Gout. "Ribosomal protein S6 kinase 1 interacts with and is ubiquitinated by ubiquitin ligase ROC1." Biochemical and Biophysical Research Communications 369, no. 2 (May 2008): 339–43. http://dx.doi.org/10.1016/j.bbrc.2008.02.016.

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13

Zhang, Jingyang, Shuo Li, Zhaoyang Shang, Shan Lin, Peng Gao, Yi Zhang, Shuaiheng Hou, et al. "Targeting the overexpressed ROC1 induces G2 cell cycle arrest and apoptosis in esophageal cancer cells." Oncotarget 8, no. 17 (March 16, 2017): 29125–37. http://dx.doi.org/10.18632/oncotarget.16250.

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14

Dou, Mingzhu, Shuai Cheng, Baotian Zhao, Yuanhu Xuan, and Minglong Shao. "The Indeterminate Domain Protein ROC1 Regulates Chilling Tolerance via Activation of DREB1B/CBF1 in Rice." International Journal of Molecular Sciences 17, no. 3 (February 25, 2016): 233. http://dx.doi.org/10.3390/ijms17030233.

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15

Higa, Leigh Ann A., Ivailo S. Mihaylov, Damon P. Banks, Jianyu Zheng, and Hui Zhang. "Radiation-mediated proteolysis of CDT1 by CUL4–ROC1 and CSN complexes constitutes a new checkpoint." Nature Cell Biology 5, no. 11 (October 26, 2003): 1008–15. http://dx.doi.org/10.1038/ncb1061.

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16

Hu, Jian, Chad M. McCall, Tomohiko Ohta, and Yue Xiong. "Targeted ubiquitination of CDT1 by the DDB1–CUL4A–ROC1 ligase in response to DNA damage." Nature Cell Biology 6, no. 10 (September 26, 2004): 1003–9. http://dx.doi.org/10.1038/ncb1172.

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17

He, Y. J., C. M. McCall, J. Hu, Y. Zeng, and Y. Xiong. "DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4-ROC1 ubiquitin ligases." Genes & Development 20, no. 21 (November 1, 2006): 2949–54. http://dx.doi.org/10.1101/gad.1483206.

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18

Jia, Lijun, and Yi Sun. "RBX1/ROC1-SCF E3 ubiquitin ligase is required for mouse embryogenesis and cancer cell survival." Cell Division 4, no. 1 (2009): 16. http://dx.doi.org/10.1186/1747-1028-4-16.

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19

Nai, Gisele, and Mariângela Marques. "Role of ROC1 protein in the control of cyclin D1 protein expression in skin melanomas." Pathology - Research and Practice 207, no. 3 (March 2011): 174–81. http://dx.doi.org/10.1016/j.prp.2011.01.001.

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20

Ozturk, N., S. J. VanVickle-Chavez, L. Akileswaran, R. N. Van Gelder, and A. Sancar. "Ramshackle (Brwd3) promotes light-induced ubiquitylation of Drosophila Cryptochrome by DDB1-CUL4-ROC1 E3 ligase complex." Proceedings of the National Academy of Sciences 110, no. 13 (March 11, 2013): 4980–85. http://dx.doi.org/10.1073/pnas.1303234110.

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21

Ruer, Ségolène, Silke Stender, Alain Filloux, and Sophie de Bentzmann. "Assembly of Fimbrial Structures in Pseudomonas aeruginosa: Functionality and Specificity of Chaperone-Usher Machineries." Journal of Bacteriology 189, no. 9 (February 9, 2007): 3547–55. http://dx.doi.org/10.1128/jb.00093-07.

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ABSTRACT Fimbrial or nonfimbrial adhesins assembled by the bacterial chaperone-usher pathway have been demonstrated to play a key role in pathogenesis. Such an assembly mechanism has been exemplified in uropathogenic Escherichia coli strains with the Pap and the Fim systems. In Pseudomonas aeruginosa, three gene clusters (cupA, cupB, and cupC) encoding chaperone-usher pathway components have been identified in the genome sequence of the PAO1 strain. The Cup systems differ from the Pap or Fim systems, since they obviously lack numbers of genes encoding fimbrial subunits. Nevertheless, the CupA system has been demonstrated to be involved in biofilm formation on solid surfaces, whereas the role of the CupB and CupC systems in biofilm formation could not be clearly elucidated. Moreover, these gene clusters were described as poorly expressed under standard laboratory conditions. The cupB and cupC clusters are directly under the control of a two-component regulatory system designated RocA1/S1/R. In this study, we revealed that Roc1-dependent induction of the cupB and cupC genes resulted in a high level of biofilm formation, with CupB and CupC acting with synergy in clustering bacteria for microcolony formation. Very importantly, this phenotype was associated with the assembly of cell surface fimbriae visualized by electron microscopy. Finally, we observed that the CupB and CupC systems are specialized in the assembly of their own fimbrial subunits and are not exchangeable.

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22

Morimoto, Mitsuru, Tamotsu Nishida, Yudai Nagayama, and Hideyo Yasuda. "Nedd8-modification of Cul1 is promoted by Roc1 as a Nedd8-E3 ligase and regulates its stability." Biochemical and Biophysical Research Communications 301, no. 2 (February 2003): 392–98. http://dx.doi.org/10.1016/s0006-291x(02)03051-6.

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23

Tan, Peilin, Serge Y. Fuchs, Angus Chen, Kenneth Wu, Carlos Gomez, Ze’ev Ronai, and Zhen-Qiang Pan. "Recruitment of a ROC1–CUL1 Ubiquitin Ligase by Skp1 and HOS to Catalyze the Ubiquitination of IκBα." Molecular Cell 3, no. 4 (April 1999): 527–33. http://dx.doi.org/10.1016/s1097-2765(00)80481-5.

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24

Ohta, Tomohiko, Jennifer J. Michel, Arndt J. Schottelius, and Yue Xiong. "ROC1, a Homolog of APC11, Represents a Family of Cullin Partners with an Associated Ubiquitin Ligase Activity." Molecular Cell 3, no. 4 (April 1999): 535–41. http://dx.doi.org/10.1016/s1097-2765(00)80482-7.

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25

Wu, Kenneth, Angus Chen, and Zhen-Qiang Pan. "Conjugation of Nedd8 to CUL1 Enhances the Ability of the ROC1-CUL1 Complex to Promote Ubiquitin Polymerization." Journal of Biological Chemistry 275, no. 41 (July 31, 2000): 32317–24. http://dx.doi.org/10.1074/jbc.m004847200.

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26

Krönke, Jan, Anupama Narla, Slater N. Hurst, Namrata Udeshi, Monica Schenone, Marie McConkey, Peter Grauman, et al. "Inhibition of the CRBN-DDB1-CUL4-ROC1 E3 Ubiquitin Ligase Mediates the Anti-Proliferative and Immunomodulatory Properties of Lenalidomide." Blood 120, no. 21 (November 16, 2012): 919. http://dx.doi.org/10.1182/blood.v120.21.919.919.

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Abstract Abstract 919 Lenalidomide is a highly effective drug for the treatment of del(5q) MDS and multiple myeloma, and its use in a range of other conditions is being actively explored. Despite its increasing use for the treatment of malignancies, the precise mechanism of action of lenalidomide has not been established. We sought to identify the direct protein targets of lenalidomide using a quantitative, mass spectrometry-based proteomic approach we developed. Using a validated derivative of lenalidomide immobilized to beads, we identified DDB1 as a target of the drug by affinity enrichment of protein binders and analysis by high performance LC-MS/MS. DDB1, together with CRBN, CUL4A, and ROC1, forms an E3 ubiquitin ligase known as CRBN-CRL4. We confirmed that members of the complex bind to the immobilized lenalidomide derivative, and could be competed off with soluble lenalidomide, further supporting the role of CRBN-CRL4 in the actions of lenalidomide. CRL4 targets multiple proteins for ubiquitination and subsequent proteasomal degradation, including the cell cycle regulators CDKN1A (p21) and CDKN1B (p27), as well as the DNA licensing factor CDT1. We hypothesized that lenalidomide disrupts the ubiquitination of these and other proteins, leading to increased levels of the respective targets. We found that treatment of the lenalidomide sensitive cell line MM1S and NCI-H929 increased protein levels of p21, p27 and CDT1 in a dose and time dependent manner. Furthermore, overexpression of these three targets led to growth inhibition. Similarly, knockdown of DDB1, CUL4A, ROC1 and CRBN by lentiviral shRNAs increased p21 and p27 protein levels and inhibited growth of these cell lines. Lenalidomide is also known to increase IL-2, promote erythropoiesis and inhibit TNF-alpha. We found that in activated primary human T cells, shRNA knockdown of DDB1 recapitulated the stimulatory effects of lenalidomide on IL-2 expression levels and release. We also found that shRNA knockdown of DDB1 and CRBN recapitulated the pro-erythropoietic effects of the drug with an increase in the number of colony-forming units-erythroid (CFU-E) compared to control knockdown. Experiments studying the effects on TNF-alpha are underway. To further establish that the CRBN-CRL4 complex is the target of lenalidomide, we tested a previously published mutant form of CRBN which prevents binding of the drug to the complex. Ectopic expression of this mutant CRBN conferred resistance to lenalidomide induced cell death to multiple myeloma cells. It also resulted in the loss of CFU-E production by lenalidomide. To gain further insight into how lenalidomide might disrupt the function of the CRBN-CRL4 complex, we did immunoprecipitation against CRBN with or without the drug and found that lenalidomide disrupts the formation of the complex by preventing binding of ROC1, the adaptor protein to ubiquitin charged E2 conjugating enzyme. Using in vivo and in vitro ubiquitination assays, we also demonstrated that lenalidomide inhibits the auto-ubiquitination of CRBN. We are currently performing a ubiquitin profiling experiment to identify other protein targets that might be affected by the disruption of the CRBN-CRL4 complex by lenalidomide. Our study establishes that lenalidomide's antiproliferative and immunomodulatory properties rely on binding to CRBN-CRL4 and inhibiting its function as ubiquitin ligase. Ito et al. showed 2010 that the same mechanism is also responsible for the teratogenic effects of thalidomide. The characterization of lenalidomide as a specific E3 ubiquitin ligase inhibitor will provide insight into the mechanism of therapeutic efficacy in MDS and multiple myeloma, and serves as a proof-of-concept that selective ubiquitin ligases are efficacious targets for cancer therapy. Disclosures: No relevant conflicts of interest to declare.

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27

Takedachi, Arato, Masafumi Saijo, and Kiyoji Tanaka. "DDB2 Complex-Mediated Ubiquitylation around DNA Damage Is Oppositely Regulated by XPC and Ku and Contributes to the Recruitment of XPA." Molecular and Cellular Biology 30, no. 11 (April 5, 2010): 2708–23. http://dx.doi.org/10.1128/mcb.01460-09.

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ABSTRACT UV-damaged-DNA-binding protein (UV-DDB) is a heterodimer comprised of DDB1 and DDB2 and integrated in a complex that includes a ubiquitin ligase component, cullin 4A, and Roc1. Here we show that the ubiquitin ligase activity of the DDB2 complex is required for efficient global genome nucleotide excision repair (GG-NER) in chromatin. Mutant DDB2 proteins derived from xeroderma pigmentosum group E patients are not able to mediate ubiquitylation around damaged sites in chromatin. We also found that CSN, a negative regulator of cullin-based ubiquitin ligases, dissociates from the DDB2 complex when the complex binds to damaged DNA and that XPC and Ku oppositely regulate the ubiquitin ligase activity, especially around damaged sites. Furthermore, the DDB2 complex-mediated ubiquitylation plays a role in recruiting XPA to damaged sites. These findings shed some light on the early stages of GG-NER.

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28

Han, Xiao-Ran, Naoya Sasaki, Sarah C. Jackson, Pu Wang, Zhijun Li, Matthew D. Smith, Ling Xie, et al. "CRL4DCAF1/VprBP E3 ubiquitin ligase controls ribosome biogenesis, cell proliferation, and development." Science Advances 6, no. 51 (December 2020): eabd6078. http://dx.doi.org/10.1126/sciadv.abd6078.

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Evolutionarily conserved DCAF1 is a major substrate receptor for the DDB1-CUL4-ROC1 E3 ubiquitin ligase (CRL4) and controls cell proliferation and development. The molecular basis for these functions is unclear. We show here that DCAF1 loss in multiple tissues and organs selectively eliminates proliferating cells and causes perinatal lethality, thymic atrophy, and bone marrow defect. Inducible DCAF1 loss eliminates proliferating, but not quiescent, T cells and MEFs. We identify the ribosome assembly factor PWP1 as a substrate of the CRL4DCAF1 ligase. DCAF1 loss results in PWP1 accumulation, impairing rRNA processing and ribosome biogenesis. Knockdown or overexpression of PWP1 can rescue defects or cause similar defects as DCAF1 loss, respectively, in ribosome biogenesis. DCAF1 loss increases free RPL11, resulting in L11-MDM2 association and p53 activation. Cumulatively, these results reveal a critical function for DCAF1 in ribosome biogenesis and define a molecular basis of DCAF1 function in cell proliferation and development.

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29

Wang, Hengbin, Ling Zhai, Jun Xu, Heui-Yun Joo, Sarah Jackson, Hediye Erdjument-Bromage, Paul Tempst, Yue Xiong, and Yi Zhang. "Histone H3 and H4 Ubiquitylation by the CUL4-DDB-ROC1 Ubiquitin Ligase Facilitates Cellular Response to DNA Damage." Molecular Cell 22, no. 3 (May 2006): 383–94. http://dx.doi.org/10.1016/j.molcel.2006.03.035.

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30

Wang, Yu, Mingjia Tan, Hua Li, Haomin Li, and Yi Sun. "Inactivation of SAG or ROC1 E3 Ligase Inhibits Growth and Survival of Renal Cell Carcinoma Cells: Effect of BIM." Translational Oncology 12, no. 6 (June 2019): 810–18. http://dx.doi.org/10.1016/j.tranon.2019.03.002.

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31

Tan, M., S. W. Davis, T. L. Saunders, Y. Zhu, and Y. Sun. "RBX1/ROC1 disruption results in early embryonic lethality due to proliferation failure, partially rescued by simultaneous loss of p27." Proceedings of the National Academy of Sciences 106, no. 15 (March 26, 2009): 6203–8. http://dx.doi.org/10.1073/pnas.0812425106.

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32

Shima, Yutaka, Takito Shima, Tomoki Chiba, Tatsuro Irimura, and Issay Kitabayashi. "PML Protects HIPK2 and p300 from SCF-Mediated Ubiquitin-Dependent Degradation To Activate Transcription." Blood 110, no. 11 (November 16, 2007): 2653. http://dx.doi.org/10.1182/blood.v110.11.2653.2653.

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Abstract The Pml gene is the target of t(15;17) chromosome translocation in acute promyelocytic leukemia. PML protein is known to localize in discrete nuclear speckles, named PML nuclear bodies (NBs). In NBs, PML interacts with several transcription factors, such as p53 and AML1, and their co-activators, such as HIPK2 and p300. PML activates transcription of their target genes. PML is thought to stabilize transcription factor complex and function as a mediator in transcription activation, but little is known about the molecular mechanism by which PML activates transcription. To clarify the role of PML in transcription regulation, we purified the PML complex and identified a novel F-box protein (FBP), Skp1, and Cullin1 (Cul1) in the PML complex by LC/MS/MS analysis. FBPs form SCF ubiquitin ligase complexes with Skp1, Cul1 and ROC1 and mediate recognition of specific substrates for ubiquitination. We found that the FBP that we identified here also forms a SCF complex with Skp1, Cul1 and ROC1. To identify substrates for the SCF complex, we tested several proteins that could bind to PML, and found that the FBP promotes degradation of HIPK2 and p300. These degradations were inhibited in the presence of a proteasome inhibitor, MG132. The FBP stimulated ubiquitination of HIPK2. These results suggest that the SCF promotes degradation of these proteins by the ubiquitin-proteasome pathway. The fact that the SCF is a part of the PML complex suggests that PML plays a role in the SCF-mediated degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway. In order to clarify the role of PML in degradation of HIPK2 and p300, we tested effects of PML on the degradation and found that PML inhibited the SCF-mediated degradation of HIPK2 and p300 without inhibition of ubiquitination. To clarify roles of HIPK2, PML IV and the FBP in p53-dependent transcription, we performed reporter analysis using the MDM2 promoter in H1299 cells. Since the FBP promotes degradation of HIPK2, we initially thought that the FBP might inhibit activation of p53-dependent transcription by HIPK2 and PML IV. However, the FBP, HIPK2 and PML synergistically stimulated the p53-dependent transcriptional activation. Taken together our data suggest that the SCF-induced ubiquitination of transcription co-activators HIPK2 and p300 plays a critical role in transcriptional regulation, and that PML stimulates transcription by protecting HIPK2 and p300 from ubiquitin-dependent degradation.

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33

Hirose, Yuki, Tomohiro Kitazono, Maiko Sezaki, Manabu Abe, Kenji Sakimura, Hiromasa Funato, Hiroshi Handa, Kaspar E. Vogt, and Masashi Yanagisawa. "Hypnotic effect of thalidomide is independent of teratogenic ubiquitin/proteasome pathway." Proceedings of the National Academy of Sciences 117, no. 37 (August 26, 2020): 23106–12. http://dx.doi.org/10.1073/pnas.1917701117.

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Thalidomide exerts its teratogenic and immunomodulatory effects by binding to cereblon (CRBN) and thereby inhibiting/modifying the CRBN-mediated ubiquitination pathway consisting of the Cullin4-DDB1-ROC1 E3 ligase complex. The mechanism of thalidomide’s classical hypnotic effect remains largely unexplored, however. Here we examined whether CRBN is involved in the hypnotic effect of thalidomide by generating mice harboring a thalidomide-resistant mutant allele of Crbn (Crbn YW/AA knock-in mice). Thalidomide increased non-REM sleep time in Crbn YW/AA knock-in homozygotes and heterozygotes to a similar degree as seen in wild-type littermates. Thalidomide similarly depressed excitatory synaptic transmission in the cortical slices obtained from wild-type and Crbn YW/AA homozygous knock-in mice without affecting GABAergic inhibition. Thalidomide induced Fos expression in vasopressin-containing neurons of the supraoptic nucleus and reduced Fos expression in the tuberomammillary nuclei. Thus, thalidomide’s hypnotic effect seems to share some downstream mechanisms with general anesthetics and GABAA-activating sedatives but does not involve the teratogenic CRBN-mediated ubiquitin/proteasome pathway.

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Wang, Wei, Zhihong Liu, Ping Qu, Zhengdong Zhou, Yigang Zeng, Jie Fan, Yong Liu, Yifeng Guo, and Jianxin Qiu. "Knockdown of Regulator of Cullins-1 (ROC1) Expression Induces Bladder Cancer Cell Cycle Arrest at the G2 Phase and Senescence." PLoS ONE 8, no. 5 (May 8, 2013): e62734. http://dx.doi.org/10.1371/journal.pone.0062734.

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Yang, D., L. Li, H. Liu, L. Wu, Z. Luo, H. Li, S. Zheng, et al. "Induction of autophagy and senescence by knockdown of ROC1 E3 ubiquitin ligase to suppress the growth of liver cancer cells." Cell Death & Differentiation 20, no. 2 (August 31, 2012): 235–47. http://dx.doi.org/10.1038/cdd.2012.113.

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Jia, Lijun, Maria S. Soengas, and Yi Sun. "ROC1/RBX1 E3 Ubiquitin Ligase Silencing Suppresses Tumor Cell Growth via Sequential Induction of G2-M Arrest, Apoptosis, and Senescence." Cancer Research 69, no. 12 (June 9, 2009): 4974–82. http://dx.doi.org/10.1158/0008-5472.can-08-4671.

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Goldenberg, Seth J., Thomas C. Cascio, Stuart D. Shumway, Kenneth C. Garbutt, Jidong Liu, Yue Xiong, and Ning Zheng. "Structure of the Cand1-Cul1-Roc1 Complex Reveals Regulatory Mechanisms for the Assembly of the Multisubunit Cullin-Dependent Ubiquitin Ligases." Cell 119, no. 4 (November 2004): 517–28. http://dx.doi.org/10.1016/j.cell.2004.10.019.

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Wu, Kenneth, Angus Chen, Peilin Tan, and Zhen-Qiang Pan. "The Nedd8-conjugated ROC1-CUL1 Core Ubiquitin Ligase Utilizes Nedd8 Charged Surface Residues for Efficient Polyubiquitin Chain Assembly Catalyzed by Cdc34." Journal of Biological Chemistry 277, no. 1 (October 23, 2001): 516–27. http://dx.doi.org/10.1074/jbc.m108008200.

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Furukawa, Manabu, Tomohiko Ohta, and Yue Xiong. "Activation of UBC5 Ubiquitin-conjugating Enzyme by the RING Finger of ROC1 and Assembly of Active Ubiquitin Ligases by All Cullins." Journal of Biological Chemistry 277, no. 18 (February 22, 2002): 15758–65. http://dx.doi.org/10.1074/jbc.m108565200.

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Furukawa, Manabu, Yanping Zhang, Joseph McCarville, Tomohiko Ohta, and Yue Xiong. "The CUL1 C-Terminal Sequence and ROC1 Are Required for Efficient Nuclear Accumulation, NEDD8 Modification, and Ubiquitin Ligase Activity of CUL1." Molecular and Cellular Biology 20, no. 21 (2000): 8185–97. http://dx.doi.org/10.1128/.20.21.8185-8197.2000.

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Ito, Momoyo, Naoki Sentoku, Asuka Nishimura, Soon-Kwan Hong, Yutaka Sato, and Makoto Matsuoka. "Position dependent expression of GL2-type homeobox gene, Roc1: significance for protoderm differentiation and radial pattern formation in early rice embryogenesis." Plant Journal 29, no. 4 (February 2002): 497–507. http://dx.doi.org/10.1046/j.1365-313x.2002.01234.x.

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Ribar, Balazs, Louise Prakash, and Satya Prakash. "ELA1 and CUL3 Are Required Along with ELC1 for RNA Polymerase II Polyubiquitylation and Degradation in DNA-Damaged Yeast Cells." Molecular and Cellular Biology 27, no. 8 (February 12, 2007): 3211–16. http://dx.doi.org/10.1128/mcb.00091-07.

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ABSTRACT Treatment of yeast and human cells with DNA-damaging agents elicits lysine 48-linked polyubiquitylation of Rpb1, the largest subunit of RNA polymerase II (Pol II), which targets Pol II for proteasomal degradation. However, the ubiquitin ligase (E3) responsible for Pol II polyubiquitylation has not been identified in humans or the yeast Saccharomyces cerevisiae . Here we show that elongin A (Ela1) and cullin 3 (Cul3) are required for Pol II polyubiquitylation and degradation in yeast cells, and on the basis of these and other observations, we propose that an E3 comprised of elongin C (Elc1), Ela1, Cul3, and the RING finger protein Roc1 (Rbx1) mediates this process in yeast cells. This study provides, in addition to the identification of the E3 required for Pol II polyubiquitylation and degradation in yeast cells, the first evidence for a specific function in yeast for a member of the elongin C/BC-box protein/cullin family of ligases. Also, these observations raise the distinct possibility that the elongin C-containing ubiquitin ligase, the von Hippel-Lindau tumor suppressor complex, promotes Pol II polyubiquitylation and degradation in human cells.

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Lin, Hong, Xiaozhe Zhang, Li Liu, Qiuyu Fu, Chuanlong Zang, Yan Ding, Yang Su, et al. "Basis for metabolite-dependent Cullin-RING ligase deneddylation by the COP9 signalosome." Proceedings of the National Academy of Sciences 117, no. 8 (February 11, 2020): 4117–24. http://dx.doi.org/10.1073/pnas.1911998117.

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The Cullin-RING ligases (CRLs) are the largest family of ubiquitin E3s activated by neddylation and regulated by the deneddylase COP9 signalosome (CSN). The inositol polyphosphate metabolites promote the formation of CRL–CSN complexes, but with unclear mechanism of action. Here, we provide structural and genetic evidence supporting inositol hexakisphosphate (IP6) as a general CSN cofactor recruiting CRLs. We determined the crystal structure of IP6 in complex with CSN subunit 2 (CSN2), based on which we identified the IP6-corresponding electron density in the cryoelectron microscopy map of a CRL4A–CSN complex. IP6 binds to a cognate pocket formed by conserved lysine residues from CSN2 and Rbx1/Roc1, thereby strengthening CRL–CSN interactions to dislodge the E2 CDC34/UBE2R from CRL and to promote CRL deneddylation. IP6 binding-deficient Csn2K70E/K70E knockin mice are embryonic lethal. The same mutation disabled Schizosaccharomyces pombe Csn2 from rescuing UV-hypersensitivity of csn2-null yeast. These data suggest that CRL transition from the E2-bound active state to the CSN-bound sequestered state is critically assisted by an interfacial IP6 small molecule, whose metabolism may be coupled to CRL–CSN complex dynamics.

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Appleman, Leonard J., Irene Chernova, Lequn Li, and Vassiliki Boussiotis. "CD28 Costimulation Induces Transcription of SKP2 and CKS1, the Substrate Recognition Components of the Skp1-Cullin-F-box Ubiquitin Ligase, SCFSkp2." Blood 108, no. 11 (November 16, 2006): 869. http://dx.doi.org/10.1182/blood.v108.11.869.869.

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Abstract Cellular immune responses require expansion of antigen-specific T cell clones from the pool of resting T lymphocytes that perform immune surveillance. Regulation of this proliferative potential is critical for defense against pathogens and avoidance of autoimmunity. Costimulation through the T cell receptor and accessory molecule, CD28, triggers replication of T lymphocytes in response to antigen that is mediated via both IL-2-dependent and IL-2-independent mechanisms. This event is associated with decreased abundance of the cyclin-dependent kinase inhibitor p27kip1 and increased cyclin D/cdk4 and cyclin E/cdk2 enzymatic activity. We have previously reported that in contrast to p27kip1 protein, the abundance of P27KIP mRNA transcript is unchanged in response to TCR/CD28 T cell activation. Ubiquitin-targeted degradation by the proteasome regulates the abundance of p27kip1 protein and ubiquitination of p27kip1 occurs in primary human T cells activated through the TCR and CD28. Ubiqutination of p27kip1 is mediated by a Skp1-Cullin-F-box (SCF) family ubiquitin ligase, SCFskp2. The SCFskp2 holoenzyme is comprised of the core components Roc1, Cul1, Skp1, and the substrate recognititon components, an F-box (cyclin F homology) protein, Skp2, that in cooperation with a smaller subunit, Cks1, mediates recognition of p27kip1 substrate. Targeted deletion of the murine Skp2 or Cks1 genes results in accumulation of p27kip1 in multiple cell types. T cell proliferation in response to TCR/CD3-plus-CD28 costimulation is reduced in Skp2−/− mice in comparison to wild-type controls, confirming the role of Skp2 in CD28 costimulation mediated degradation of p27kip1 and T cell proliferation. Here, we examined the mechanisms that regulate Skp2 and Cks1 abundance in primary T lymphocytes in response to TCR/CD3-plus-CD28 costimulation. Using primary human T lymphocytes we observed that the SCFskp2 core components Roc1, Cul1 and Skp1 are constitutively expressed and their levels remain unchanged upon TCR/CD3-plus-CD28 costimulation. In contrast, TCR/CD3-plus-CD28 costimulation lead to striking induction of SKP2 and CKS1 mRNA, and this event is dependent on PI3K/PKB and MEK/ERK signaling pathways. We determined that the SKP2 promoter lies directly upstream of the translation start site and contains binding sites for SP1, Elk-1 and E2F transcription factors. Mutagenesis of SP1 and Elk-1 sites abrogated TCR/CD3-plus-CD28-mediated SKP2 promoter-driven reporter activity, whereas mutagenesis of E2F site enhanced reporter activity, suggesting that SKP2 promoter may act as a node of integration for mitogenic and anti-mitogenic signals. Thus, in primary T lymphocytes CD28 costimulation can directly regulate cell cycle progression by inducing transcription of the substrate recognition components of SCFskp2 ubiquitin ligase that targets p27kip1 for degradation.

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Kobayashi, Akira, Moon-Il Kang, Hiromi Okawa, Makiko Ohtsuji, Yukari Zenke, Tomoki Chiba, Kazuhiko Igarashi, and Masayuki Yamamoto. "Oxidative Stress Sensor Keap1 Functions as an Adaptor for Cul3-Based E3 Ligase To Regulate Proteasomal Degradation of Nrf2." Molecular and Cellular Biology 24, no. 16 (August 15, 2004): 7130–39. http://dx.doi.org/10.1128/mcb.24.16.7130-7139.2004.

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ABSTRACT Transcription factor Nrf2 is a major regulator of genes encoding phase 2 detoxifying enzymes and antioxidant stress proteins in response to electrophilic agents and oxidative stress. In the absence of such stimuli, Nrf2 is inactive owing to its cytoplasmic retention by Keap1 and rapid degradation through the proteasome system. We examined the contribution of Keap1 to the rapid turnover of Nrf2 (half-life of less than 20 min) and found that a direct association between Keap1 and Nrf2 is required for Nrf2 degradation. In a series of domain function analyses of Keap1, we found that both the BTB and intervening-region (IVR) domains are crucial for Nrf2 degradation, implying that these two domains act to recruit ubiquitin-proteasome factors. Indeed, Cullin 3 (Cul3), a subunit of the E3 ligase complex, was found to interact specifically with Keap1 in vivo. Keap1 associates with the N-terminal region of Cul3 through the IVR domain and promotes the ubiquitination of Nrf2 in cooperation with the Cul3-Roc1 complex. These results thus provide solid evidence that Keap1 functions as an adaptor of Cul3-based E3 ligase. To our knowledge, Nrf2 and Keap1 are the first reported mammalian substrate and adaptor, respectively, of the Cul3-based E3 ligase system.

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Boyer, Laurent, Sara Travaglione, Loredana Falzano, Nils C. Gauthier, Michel R. Popoff, Emmanuel Lemichez, Carla Fiorentini, and Alessia Fabbri. "Rac GTPase Instructs Nuclear Factor-κB Activation by Conveying the SCF Complex and IkBα to the Ruffling Membranes." Molecular Biology of the Cell 15, no. 3 (March 2004): 1124–33. http://dx.doi.org/10.1091/mbc.e03-05-0301.

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Nuclear factor-κB (NF-κB) is a ubiquitously expressed transcription factor that plays a central role in directing a vast range of cellular functions. Its activation is controlled by the Rac GTPase and relies on the coordinated cooperation of the E3–ligase complex SCFβTrCP, composed by Skp-1/Cullin-1, Rbx/Roc1, and the β-TrCP proteins. Recently, Cullin-1 has been reported to form a complex with the activated Rac GTPase. Here, we show that the specific activation of the Rac GTPase, besides directing its own positioning, induces the relocalization of the SCF component Cullin-1 to the ruffling membranes. This occurred only if the ruffles were stimulated by the Rac GTPase and was accompanied by the repositioning to the same intracellular compartment of the SCF protein Skp-1 and the ubiquitin-like molecule Nedd-8. The SCF substrate IkBα was also directed to the ruffling membranes in a Rac-dependent way. The novelty of these findings is in respect to the demonstration that the correct positioning at the ruffling membranes is crucial for the subsequent series of events that leads to IkBα proteasomal degradation and the resultant activation of NF-κB. Consequently, this points to the role of Rac as a docking molecule in NF-κB activation.

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Chen, Ping, Xiaoting Luo, Zhihui Che, Wenli Zhang, Fuchen Liu, Daisen Hou, Dongqin Yang, and Jie Liu. "Targeting of the C-Jun/BCL-XL/P21 Axis Accelerates the Switch from Senescence to Apoptosis Upon ROC1 Knockdown in Gastric Cancer Cells." Cellular Physiology and Biochemistry 48, no. 3 (2018): 1123–38. http://dx.doi.org/10.1159/000491979.

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Carrano, Andrea C., and Michele Pagano. "Role of the F-Box Protein Skp2 in Adhesion-Dependent Cell Cycle Progression." Journal of Cell Biology 153, no. 7 (June 18, 2001): 1381–90. http://dx.doi.org/10.1083/jcb.153.7.1381.

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Cell adhesion to the extracellular matrix (ECM) is a requirement for proliferation that is typically lost in malignant cells. In the absence of adhesion, nontransformed cells arrest in G1 with increased levels of the cyclin-dependent kinase inhibitor p27. We have reported previously that the degradation of p27 requires its phosphorylation on Thr-187 and is mediated by Skp2, an F-box protein that associates with Skp1, Cul1, and Roc1/Rbx1 to form the SCFSkp2 ubiquitin ligase complex. Here, we show that the accumulation of Skp2 protein is dependent on both cell adhesion and growth factors but that the induction of Skp2 mRNA is exclusively dependent on cell adhesion to the ECM. Conversely, the expression of the other three subunits of the SCFSkp2 complex is independent of cell anchorage. Phosphorylation of p27 on Thr-187 is also not affected significantly by the loss of cell adhesion, demonstrating that increased p27 stability is not dependent on p27 dephosphorylation. Significantly, ectopic expression of Skp2 in nonadherent G1 cells resulted in p27 downregulation, entry into S phase, and cell division. The ability to induce adhesion-independent cell cycle progression was potentiated by coexpressing Skp2 with cyclin D1 but not with cyclin E, indicating that Skp2 and cyclin D1 cooperate to rescue proliferation in suspension cells. Our study shows that Skp2 is a key target of ECM signaling that controls cell proliferation.

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McCall, Chad M., Paula L. Miliani de Marval, Paul D. Chastain, Sarah C. Jackson, Yizhou J. He, Yojiro Kotake, Jeanette Gowen Cook, and Yue Xiong. "Human Immunodeficiency Virus Type 1 Vpr-Binding Protein VprBP, a WD40 Protein Associated with the DDB1-CUL4 E3 Ubiquitin Ligase, Is Essential for DNA Replication and Embryonic Development." Molecular and Cellular Biology 28, no. 18 (July 7, 2008): 5621–33. http://dx.doi.org/10.1128/mcb.00232-08.

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ABSTRACT Damaged DNA binding protein 1, DDB1, bridges an estimated 90 or more WD40 repeats (DDB1-binding WD40, or DWD proteins) to the CUL4-ROC1 catalytic core to constitute a potentially large number of E3 ligase complexes. Among these DWD proteins is the human immunodeficiency virus type 1 (HIV-1) Vpr-binding protein VprBP, whose cellular function has yet to be characterized but has recently been found to mediate Vpr-induced G2 cell cycle arrest. We demonstrate here that VprBP binds stoichiometrically with DDB1 through its WD40 domain and through DDB1 to CUL4A, subunits of the COP9/signalsome, and DDA1. The steady-state level of VprBP remains constant during interphase and decreases during mitosis. VprBP binds to chromatin in a DDB1-independent and cell cycle-dependent manner, increasing from early S through G2 before decreasing to undetectable levels in mitotic and G1 cells. Silencing VprBP reduced the rate of DNA replication, blocked cells from progressing through the S phase, and inhibited proliferation. VprBP ablation in mice results in early embryonic lethality. Conditional deletion of the VprBP gene in mouse embryonic fibroblasts results in severely defective progression through S phase and subsequent apoptosis. Our studies identify a previously unknown function of VprBP in S-phase progression and suggest the possibility that HIV-1 Vpr may divert an ongoing chromosomal replication activity to facilitate viral replication.

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Ulane, Christina M., Alex Kentsis, Cristian D. Cruz, Jean-Patrick Parisien, Kristi L. Schneider, and Curt M. Horvath. "Composition and Assembly of STAT-Targeting Ubiquitin Ligase Complexes: Paramyxovirus V Protein Carboxyl Terminus Is an Oligomerization Domain." Journal of Virology 79, no. 16 (August 15, 2005): 10180–89. http://dx.doi.org/10.1128/jvi.79.16.10180-10189.2005.

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ABSTRACT Transcription regulators STAT1 and STAT2 are key components of the interferon signaling system leading to innate antiviral immunity. The related STAT3 protein is a regulator of interleukin-6-type cytokine signals and can contribute to both cell growth and death important for cancer gene regulation and tumor survival. These three STAT proteins are targeted for proteasome-mediated degradation by RNA viruses in the Rubulavirus genus of the Paramyxoviridae. A single viral protein, the V protein, assembles STAT-specific ubiquitin ligase complexes from cellular components. Simian virus 5 (SV5) targets STAT1, human parainfluenza virus 2 targets STAT2, and mumps virus targets both STAT1 and STAT3. Analysis of the V-dependent degradation complex (VDC) composition and assembly revealed several features contributing to targeting specificity. SV5 and mumps V proteins require STAT2 to recruit the STAT1 target, yet mumps V protein binds STAT3 independent of STAT1 and STAT2. All Rubulavirus V proteins tested require cellular DDB1 to target STATs for degradation but differ in the use of Roc1, which is essential for mumps V STAT3 targeting. Protein interaction analysis reveals that paramyxovirus V proteins can homo- and heterooligomerize and that the conserved cysteine-rich zinc-binding C-terminal domain is necessary and sufficient for oligomerization. Purified SV5 V protein spontaneously assembles into spherical macromolecular particles, and similar particles constitute SV5 and mumps VDC preparations.

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