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Vol. 17, Issue 11, 4606-4618, November 2006
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*Department of Anatomy and Cell Biology, Indiana University School of Medicine, Evansville, IN 47712; Departments of Physiology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390; and Department of Histology and Embryology, Medical University of Warsaw, 02-004 Warsaw, Poland
Submitted May 18, 2006;
Revised August 3, 2006;
Accepted August 7, 2006
Monitoring Editor: Jeffrey Brodsky
Valosin-containing protein (VCP; p97; cdc48 in yeast) is a hexameric ATPase of the AAA family (ATPases with multiple cellular activities) involved in multiple cellular functions, including degradation of proteins by the ubiquitin (Ub)–proteasome system (UPS). We examined the consequences of the reduction of VCP levels after RNA interference (RNAi) of VCP. A new stringent method of microarray analysis demonstrated that only four transcripts were nonspecifically affected by RNAi, whereas 
30 transcripts were affected in response to reduced VCP levels in a sequence-independent manner. These transcripts encoded proteins involved in endoplasmic reticulum (ER) stress, apoptosis, and amino acid starvation. RNAi of VCP promoted the unfolded protein response, without eliciting a cytosolic stress response. RNAi of VCP inhibited the degradation of R-GFP (green fluorescent protein) and Ub-G76V-GFP, two cytoplasmic reporter proteins degraded by the UPS, and of 
chain of the T-cell receptor, an established substrate of the ER-associated degradation (ERAD) pathway. Surprisingly, RNAi of VCP had no detectable effect on the degradation of two other ERAD substrates, 1-antitrypsin and 
CD3. These results indicate that VCP is required for maintenance of normal ER structure and function and mediates the degradation of some proteins via the UPS, but is dispensable for the UPS-dependent degradation of some ERAD substrates.
Address correspondence to: Cezary Wójcik (cwojcik{at}iupui.edu) or George N. DeMartino (george.demartino{at}utsouthwestern.edu)
Abbreviations used: AAA, ATPases with multiple cellular activities; BFA, brefeldin A; ERAD, endoplasmic reticulum-associated degradation; GFP, green fluorescent protein; R-GFP, GFP with the N-terminal Met replaced by Arg; siRNA, small interfering RNA; TCR, chain of the T-cell receptor; Ub-G76V-GFP, GFP with a noncleavable, mutated (Gly76Val) Ub attached to its N terminus; UFD, ubiquitin-fusion degradation; UPR, unfolded protein response; UPS, ubiquitin-proteasome system; VCP, valosin-containing protein.
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