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JCS ePress
online publication date 2 Dec 2003
doi: 10.1242/jcs.00841
Research Article
RNA interference of valosin-containing protein (VCP/p97) reveals multiple cellular roles linked to ubiquitin/proteasome-dependent proteolysis
Cezary Wójcik,
Mihiro Yano,
and
George N. DeMartino*
* Author for correspondence (e-mail: george.demartino{at}utsouthwestern.edu)
We have used RNA interference (RNAi) to examine the functional relationship between valosin-containing protein (VCP/p97/Cdc48p/TER94) ATPase and the ubiquitin-proteasome system (UPS) in Drosophila S2 and human HeLa cells. In both cell types, RNAi of VCP (and, to a lesser extent, of certain VCP-interacting proteins) caused significant accumulation of high-molecular-weight conjugates of ubiquitin, an indication of inhibited UPS function. However, decreased VCP levels did not directly inhibit proteasome activity. In HeLa cells, polyubiquitinated proteins accumulated as dispersed aggregates rather than as single aggresomes, even in the presence of proteasome inhibitors, which normally promote aggresome formation. RNAi of VCP caused extensive vacuolization of the cytoplasm, and proteasome inhibitors exaggerated this feature. RNAi of VCP had little effect on S2 cell proliferation but blocked cell-cycle progression and induced mitotic abnormalities and apoptosis in HeLa cells. These results indicate that VCP plays an important general role in mediating the function of the UPS, probably by interacting with potential proteasome substrates before they are degraded by the proteasome.
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|
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|
|
|
|
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283(44):
30289 - 30299.
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[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Lu, Y. Yang, E. M. Allister, N. Wijesekara, and M. B. Wheeler
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|
|
|
|
|
|
|
R. S. Marshall, N. A. Jolliffe, A. Ceriotti, C. J. Snowden, J. M. Lord, L. Frigerio, and L. M. Roberts
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283(23):
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[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Boyault, Y. Zhang, S. Fritah, C. Caron, B. Gilquin, S. H. Kwon, C. Garrido, T.-P. Yao, C. Vourc'h, P. Matthias, et al.
HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates
Genes & Dev.,
September 1, 2007;
21(17):
2172 - 2181.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Bish and M. P. Myers
Werner Helicase-interacting Protein 1 Binds Polyubiquitin via Its Zinc Finger Domain
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282(32):
23184 - 23193.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Kobayashi, A. Manno, and A. Kakizuka
Involvement of valosin-containing protein (VCP)/p97 in the formation and clearance of abnormal protein aggregates
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12(7):
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|
|
|
|
|
|
|
G. Zhao, X. Zhou, L. Wang, G. Li, H. Schindelin, and W. J. Lennarz
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104(21):
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|
|
|
|
|
|
|
S. Heubes and O. Stemmann
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120(8):
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|
|
|
|
|
|
|
M. Jing, J. Bohl, N. Brimer, M. Kinter, and S. B. Vande Pol
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81(5):
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|
|
|
|
|
|
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C. Wojcik, M. Rowicka, A. Kudlicki, D. Nowis, E. McConnell, M. Kujawa, and G. N. DeMartino
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17(11):
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|
|
|
|
|
|
|
E. G. Mimnaugh, W. Xu, M. Vos, X. Yuan, and L. Neckers
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4(9):
667 - 681.
[Abstract]
[Full Text]
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|
|
|
|
|
|
|
L. Guyant-Marechal, A. Laquerriere, C. Duyckaerts, C. Dumanchin, J. Bou, F. Dugny, I. Le Ber, T. Frebourg, D. Hannequin, and D. Campion
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August 22, 2006;
67(4):
644 - 651.
[Abstract]
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|
|
|
|
|
|
|
F. Vandermoere, I. El Yazidi-Belkoura, C. Slomianny, Y. Demont, G. Bidaux, E. Adriaenssens, J. Lemoine, and H. Hondermarck
The Valosin-containing Protein (VCP) Is a Target of Akt Signaling Required for Cell Survival
J. Biol. Chem.,
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281(20):
14307 - 14313.
[Abstract]
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|
|
|
|
|
|
|
J. Wu, A. Katrekar, L. A. Honigberg, A. M. Smith, M. T. Conn, J. Tang, D. Jeffery, K. Mortara, J. Sampang, S. R. Williams, et al.
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J. Biol. Chem.,
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281(16):
11002 - 11010.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Wang, Y. Ye, W. Lencer, and T. H. Hansen
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281(13):
8636 - 8644.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Laser, L. Conforti, G. Morreale, T. G.M. Mack, M. Heyer, J. E. Haley, T. M. Wishart, B. Beirowski, S. A. Walker, G. Haase, et al.
The Slow Wallerian Degeneration Protein, WldS, Binds Directly to VCP/p97 and Partially Redistributes It within the Nucleus
Mol. Biol. Cell,
March 1, 2006;
17(3):
1075 - 1084.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. Mullally, T. Chernova, and K. D. Wilkinson
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February 1, 2006;
26(3):
822 - 830.
[Abstract]
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|
|
|
|
|
|
|
A. Gerega, B. Rockel, J. Peters, T. Tamura, W. Baumeister, and P. Zwickl
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J. Biol. Chem.,
December 30, 2005;
280(52):
42856 - 42862.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Noguchi, T. Takata, Y. Kimura, A. Manno, K. Murakami, M. Koike, H. Ohizumi, S. Hori, and A. Kakizuka
ATPase Activity of p97/Valosin-containing Protein Is Regulated by Oxidative Modification of the Evolutionally Conserved Cysteine 522 Residue in Walker A Motif
J. Biol. Chem.,
December 16, 2005;
280(50):
41332 - 41341.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. J. Alzayady, M. M. Panning, G. G. Kelley, and R. J. H. Wojcikiewicz
Involvement of the p97-Ufd1-Npl4 Complex in the Regulated Endoplasmic Reticulum-associated Degradation of Inositol 1,4,5-Trisphosphate Receptors
J. Biol. Chem.,
October 14, 2005;
280(41):
34530 - 34537.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Livingstone, H. Ruan, J. Weiner, K. R. Clauser, P. Strack, S. Jin, A. Williams, H. Greulich, J. Gardner, M. Venere, et al.
Valosin-Containing Protein Phosphorylation at Ser784 in Response to DNA Damage
Cancer Res.,
September 1, 2005;
65(17):
7533 - 7540.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Kothe, Y. Ye, J. S. Wagner, H. E. De Luca, E. Kern, T. A. Rapoport, and W. I. Lencer
Role of p97 AAA-ATPase in the Retrotranslocation of the Cholera Toxin A1 Chain, a Non-ubiquitinated Substrate
J. Biol. Chem.,
July 29, 2005;
280(30):
28127 - 28132.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Lundgren, P. Masson, Z. Mirzaei, and P. Young
Identification and Characterization of a Drosophila Proteasome Regulatory Network
Mol. Cell. Biol.,
June 1, 2005;
25(11):
4662 - 4675.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Ishigaki, N. Hishikawa, J.-i. Niwa, S.-i. Iemura, T. Natsume, S. Hori, A. Kakizuka, K. Tanaka, and G. Sobue
Physical and Functional Interaction between Dorfin and Valosin-containing Protein That Are Colocalized in Ubiquitylated Inclusions in Neurodegenerative Disorders
J. Biol. Chem.,
December 3, 2004;
279(49):
51376 - 51385.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Shiozawa, N. Maita, K. Tomii, A. Seto, N. Goda, Y. Akiyama, T. Shimizu, M. Shirakawa, and H. Hiroaki
Structure of the N-terminal Domain of PEX1 AAA-ATPase: CHARACTERIZATION OF A PUTATIVE ADAPTOR-BINDING DOMAIN
J. Biol. Chem.,
November 26, 2004;
279(48):
50060 - 50068.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Zhong, Y. Shen, P. Ballar, A. Apostolou, R. Agami, and S. Fang
AAA ATPase p97/Valosin-containing Protein Interacts with gp78, a Ubiquitin Ligase for Endoplasmic Reticulum-associated Degradation
J. Biol. Chem.,
October 29, 2004;
279(44):
45676 - 45684.
[Abstract]
[Full Text]
[PDF]
|
|
|
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