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Science 23 April 1999:
Vol. 284. no. 5414, pp. 657 - 661
DOI: 10.1126/science.284.5414.657
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Reports

Rbx1, a Component of the VHL Tumor Suppressor Complex and SCF Ubiquitin Ligase

T. Kamura, 12 D. M. Koepp, 345 M. N. Conrad, 2 D. Skowyra, 4 R. J. Moreland, 2 O. Iliopoulos, 67 W. S. Lane, 9 W. G. Kaelin Jr., 68 S. J. Elledge, 345 R. C. Conaway, 2 J. W. Harper, 4 J. W. Conaway 1210*

The von Hippel-Lindau (VHL) tumor suppressor gene is mutated in most human kidney cancers. The VHL protein is part of a complex that includes Elongin B, Elongin C, and Cullin-2, proteins associated with transcriptional elongation and ubiquitination. Here it is shown that the endogenous VHL complex in rat liver also includes Rbx1, an evolutionarily conserved protein that contains a RING-H2 fingerlike motif and that interacts with Cullins. The yeast homolog of Rbx1 is a subunit and potent activator of the Cdc53-containing SCFCdc4 ubiquitin ligase required for ubiquitination of the cyclin-dependent kinase inhibitor Sic1 and for the G1 to S cell cycle transition. These findings provide a further link between VHL and the cellular ubiquitination machinery.

1 Howard Hughes Medical Institute,
2 Program in Molecular and Cell Biology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
3 Howard Hughes Medical Institute,
4 Verna and Marrs McLean Department of Biochemistry,
5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
6 Dana-Farber Cancer Institute,
7 Brigham and Women's Hospital,
8 Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
9 Harvard Microchemistry Facility, Harvard University, Cambridge, MA 02138, USA.
10 Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA.
*   To whom correspondence should be addressed. E-mail: conawayj{at}omrf.ouhsc.edu

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The Hsp70 and TRiC/CCT Chaperone Systems Cooperate In Vivo To Assemble the Von Hippel-Lindau Tumor Suppressor Complex.
M. W. Melville, A. J. McClellan, A. S. Meyer, A. Darveau, and J. Frydman (2003)
Mol. Cell. Biol. 23, 3141-3151
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Cop9/signalosome subunits and Pcu4 regulate ribonucleotide reductase by both checkpoint-dependent and -independent mechanisms.
C. Liu, K. A. Powell, K. Mundt, L. Wu, A. M. Carr, and T. Caspari (2003)
Genes & Dev. 17, 1130-1140
   Abstract »    Full Text »    PDF »
TIP120A Associates with Cullins and Modulates Ubiquitin Ligase Activity.
K.-W. Min, J.-W. Hwang, J.-S. Lee, Y. Park, T.-a. Tamura, and J.-B. Yoon (2003)
J. Biol. Chem. 278, 15905-15910
   Abstract »    Full Text »    PDF »
MAPK Signaling Up-regulates the Activity of Hypoxia-inducible Factors by Its Effects on p300.
N. Sang, D. P. Stiehl, J. Bohensky, I. Leshchinsky, V. Srinivas, and J. Caro (2003)
J. Biol. Chem. 278, 14013-14019
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von Hippel-Lindau protein binds hyperphosphorylated large subunit of RNA polymerase II through a proline hydroxylation motif and targets it for ubiquitination.
A. V. Kuznetsova, J. Meller, P. O. Schnell, J. A. Nash, M. L. Ignacak, Y. Sanchez, J. W. Conaway, R. C. Conaway, and M. F. Czyzyk-Krzeska (2003)
PNAS 100, 2706-2711
   Abstract »    Full Text »    PDF »
Overproduction of Polypeptides Corresponding to the Amino Terminus of the F-Box Proteins Cdc4p and Met30p Inhibits Ubiquitin Ligase Activities of Their SCF Complexes.
C. Dixon, L. E. Brunson, M. M. Roy, D. Smothers, M. G. Sehorn, and N. Mathias (2003)
Eukaryot. Cell 2, 123-133
   Abstract »    Full Text »    PDF »
The AtRbx1 Protein Is Part of Plant SCF Complexes, and Its Down-regulation Causes Severe Growth and Developmental Defects.
E. Lechner, D. Xie, S. Grava, E. Pigaglio, S. Planchais, J. A. H. Murray, Y. Parmentier, J. Mutterer, B. Dubreucq, W.-H. Shen, et al. (2002)
J. Biol. Chem. 277, 50069-50080
   Abstract »    Full Text »    PDF »
A Positive Regulatory Role for Suppressor of Cytokine Signaling 1 in IFN-{gamma}-Induced MHC Class II Expression in Fibroblasts.
S. Ilangumaran, D. Finan, J. La Rose, J. Raine, A. Silverstein, P. De Sepulveda, and R. Rottapel (2002)
J. Immunol. 169, 5010-5020
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Leu-574 of HIF-1alpha Is Essential for the von Hippel-Lindau (VHL)-mediated Degradation Pathway.
L. E. Huang, E. A. Pete, M. Schau, J. Milligan, and J. Gu (2002)
J. Biol. Chem. 277, 41750-41755
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The p127 Subunit (DDB1) of the UV-DNA Damage Repair Binding Protein Is Essential for the Targeted Degradation of STAT1 by the V Protein of the Paramyxovirus Simian Virus 5.
J. Andrejeva, E. Poole, D. F. Young, S. Goodbourn, and R. E. Randall (2002)
J. Virol. 76, 11379-11386
   Abstract »    Full Text »    PDF »
The pressure rises: update on the genetics of phaeochromocytoma.
E. R. Maher and C. Eng (2002)
Hum. Mol. Genet. 11, 2347-2354
   Abstract »    Full Text »    PDF »
Understanding familial and non-familial renal cell cancer.
D. Bodmer, W. van den Hurk, J. J. M. van Groningen, M. J. Eleveld, G. J. M. Martens, M. A. J. Weterman, and A. Geurts van Kessel (2002)
Hum. Mol. Genet. 11, 2489-2498
   Abstract »    Full Text »    PDF »
Multiple Ubiquitin Ligase-Mediated Processes Require COP9 Signalosome and AXR1 Function.
C. Schwechheimer, G. Serino, and X.-W. Deng (2002)
PLANT CELL 14, 2553-2563
   Abstract »    Full Text »    PDF »
Distinct protein degradation mechanisms mediated by Cul1 and Cul3 controlling Ci stability in Drosophila eye development.
C.-Y. Ou, Y.-F. Lin, Y.-J. Chen, and C.-T. Chien (2002)
Genes & Dev. 16, 2403-2414
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Retinal Hemangioblastoma in von Hippel-Lindau Disease: A Clinical and Molecular Study.
H. Dollfus, P. Massin, P. Taupin, C. Nemeth, S. Amara, S. Giraud, C. Beroud, P. Dureau, A. Gaudric, P. Landais, et al. (2002)
Invest. Ophthalmol. Vis. Sci. 43, 3067-3074
   Abstract »    Full Text »    PDF »
The anaphase-promoting complex: it's not just for mitosis any more.
J. W. Harper, J. L. Burton, and M. J. Solomon (2002)
Genes & Dev. 16, 2179-2206
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Role of the Arabidopsis RING-H2 Protein RBX1 in RUB Modification and SCF Function.
W. M. Gray, H. Hellmann, S. Dharmasiri, and M. Estelle (2002)
PLANT CELL 14, 2137-2144
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Analysis of the Adenovirus E1B-55K-Anchored Proteome Reveals Its Link to Ubiquitination Machinery.
J. N. Harada, A. Shevchenko, A. Shevchenko, D. C. Pallas, and A. J. Berk (2002)
J. Virol. 76, 9194-9206
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A Molecular Basis for Stabilization of the von Hippel-Lindau (VHL) Tumor Suppressor Protein by Components of the VHL Ubiquitin Ligase.
T. Kamura, C. S. Brower, R. C. Conaway, and J. W. Conaway (2002)
J. Biol. Chem. 277, 30388-30393
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Mammalian mediator subunit mMED8 is an Elongin BC-interacting protein that can assemble with Cul2 and Rbx1 to reconstitute a ubiquitin ligase.
C. S. Brower, S. Sato, C. Tomomori-Sato, T. Kamura, A. Pause, R. Stearman, R. D. Klausner, S. Malik, W. S. Lane, I. Sorokina, et al. (2002)
PNAS 99, 10353-10358
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Oxygen-Dependent Ubiquitination and Degradation of Hypoxia-Inducible Factor Requires Nuclear-Cytoplasmic Trafficking of the von Hippel-Lindau Tumor Suppressor Protein.
I. Groulx and S. Lee (2002)
Mol. Cell. Biol. 22, 5319-5336
   Abstract »    Full Text »    PDF »


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