Disease relevance of VCP

• VCP (p97) regulates NFkappaB signaling pathway, which is important for metastasis of osteosarcoma cell line [1].
• Physical and functional interaction between Dorfin and Valosin-containing protein that are colocalized in ubiquitylated inclusions in neurodegenerative disorders [2].
• Further, VCP is the mammalian homologue of yeast Cdc48p (ref. 3) and is a member of a larger gene family that includes putative ATP-binding proteins involved in vesicle transport and fusion, 26S proteasome function, regulation of the expression of human immunodeficiency virus, and assembly of peroxisomes [3].
• Here, we report the central nervous system autopsy findings in a 55-year-old German patient with inclusion body myopathy and frontotemporal dementia who harbors a heterozygous R155C missense mutation residing in the N-terminal CDC48 domain of VCP, which is involved in ubiquitin binding [4].
• Multivariate analysis revealed VCP expression level, tumor multiplicity, and degree of fibrosis in the noncancerous liver tissue to be independent prognosticators for disease-free and overall survival [5].

High impact information on VCP

• VCP is associated with a variety of cellular activities, including cell cycle control, membrane fusion and the ubiquitin-proteasome degradation pathway [6].
• Identification of VCP as causing IBMPFD has important implications for other inclusion-body diseases, including myopathies, dementias and Paget disease of bone (PDB), as it may define a new common pathological ubiquitin-based pathway [6].
• Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) is a dominant progressive disorder that maps to chromosome 9p21.1-p12 [6].
• We investigated 13 families with IBMPFD linked to chromosome 9 using a candidate-gene approach [6].
• We found six missense mutations in the gene encoding valosin-containing protein (VCP, a member of the AAA-ATPase superfamily) exclusively in all 61 affected individuals [6].

Chemical compound and disease context of VCP

• VCP was found to be constitutively phosphorylated on tyrosine in Rous sarcoma virus-transformed fibroblasts [7].
• PURPOSE: From 1986 to 1992, "eight-drugs-in-one-day" (8-in-1) chemotherapy both before and after radiation therapy (XRT) (54 Gy tumor/36 Gy neuraxis) was compared with vincristine, lomustine (CCNU), and prednisone (VCP) after XRT in children with untreated, high-stage medulloblastoma (MB) [8].
• Chimeric Envs between HIV-2/vcp and a CD4-dependent clone of HIV-2/NIHz as well as site-directed Env mutations implicated a positively charged amino acid (lysine or arginine) at position 427 in the C4 region of the HIV-2/vcp env gene product (VCP) gp120 as a key determinant for this phenotype [9].
• p97 is a cell-surface glycoprotein that is present in most human melanomas but only in trace amounts in normal adult tissues [10].
• This cell surface material released by mild trypsin digestion from galactose-labeled human teratocarcinoma cells, Tera I and PA1, was digested extensively with pronase [11].

Biological context of VCP

• Although we were unable to determine the exact site of phosphorylation of VCP, we did confirm, using a cross-immunoprecipitation approach, that this protein is tyrosine phosphorylated during capacitation [12].
• The amplified human fragment served as probe on Southern blots of hybrid DNAs to determine that the human VCP locus maps to chromosome region 9pter-q34 [13].
• Quantitative reverse transcription polymerase chain reaction analysis showed higher VCP mRNA expression in malignant PENs (n = 5) than benign cases (n = 5) (p < 0.05) [14].
• A cell-free system that mimics the reassembly of Golgi stacks at the end of mitosis requires two ATPases, NSF and p97, to rebuild Golgi cisternae [15].
• VCP has been implicated in control of a variety of membrane functions, including membrane fusions, and is a regulator of the cell cycle [16].

Anatomical context of VCP

• VCP staining intensity in tumor cells was categorized as weaker (level 1) or equal to stronger (level 2) compared to nontumorous islet cells [14].
• Tom34 was found primarily in the cytosol while VCP and ATP6M were found in the cytosol as well as in nonmitochondrial organelles [17].
• Furthermore, this is the first report demonstrating that mutant VCP leads to a novel form of dilatative cardiomyopathy with inclusion bodies [18].
• Pathological consequences of VCP mutations on human striated muscle [18].
• We constructed and characterized PC12 cells expressing wild-type p97/VCP and p97(K524A), a D2 domain mutant [19].

Associations of VCP with chemical compounds

• The inhibition of the major stress-inducible transcription factor CHOP (CCAAT/enhancer-binding protein homologous protein)/GADD153 together with bortezomib was most effective in repressing NFkappaB-mediated IL8 activation compared with interference of VCP, MLN-273 (proteasome inhibitor), or 4-phenylbutyrate (histone deacetylase inhibitor) [20].
• Interference in the VCP-CFTR complex promoted accumulation of immature CFTR in the ER and partial rescue of functional chloride channels to the cell surface [20].
• Glutathione S-transferase pull-down experiments showed that all three VCP mutations do not affect the binding to Ufd1, Npl4 and ataxin-3 [18].
• Moreover, induction of wild type PTPH1 resulted in specific dephosphorylation of VCP without changing the overall phosphotyrosine profile of the cells [16].
• Glycerol gradient centrifugation analysis showed that endogenous Dorfin consisted of a 400-600-kDa complex and was co-immunoprecipitated with endogenous VCP [2].

Physical interactions of VCP

• How the ubiquitination machinery is recruited to the p97/Derlin/VIMP complex is unclear [21].
• Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates [22].
• These results suggest that hFAF1 binding to ubiquitinated protein and VCP is involved in the ubiquitin-proteasome pathway [23].
• In vitro experiments showed that Dorfin interacted directly with VCP through its C-terminal region [2].
• The PUB domain functions as a p97 binding module in human peptide N-glycanase [24].

Regulatory relationships of VCP

• In vivo studies with Drosophila models confirmed that VCP selectively modulates aggregation and neurotoxicity induced by pathogenic Atx-3 [25].
• Pre-B-cell leukemia transcription factor 1 regulates expression of valosin-containing protein, a gene involved in cancer growth [26].

Other interactions of VCP

• These findings indicate that Derlin-2 and -3 provide the missing link between EDEM and p97 in the process of degrading misfolded glycoproteins [27].
• During retrotranslocation, a substrate first interacts with Derlin-1 before p97 and other factors join the complex [21].
• Human Fas-associated factor 1, interacting with ubiquitinated proteins and valosin-containing protein, is involved in the ubiquitin-proteasome pathway [23].
• NSF and p97/VCP: similar at first, different at last [28].
• METHODS: The Ki-67 LI and VCP expression at the mRNA and protein level were evaluated in 32 patients (12 male and 20 female) with PENs aged from 22 to 73 years (median 49 years) [14].

Analytical, diagnostic and therapeutic context of VCP

• RESULTS: Five cases (15.6%) showed level 1 and 25 (84.4%) level 2 VCP expression by immunohistochemistry [14].
• To map the human VCP sequence, a human-specific probe was made by RT-PCR of human mRNA using oligonucleotide primers from conserved regions of the porcine sequence [13].
• VCP level was an indicator for disease-free survival in each early- (I and II) and advanced- (III and IV) stage group of pathologic tumor-node-metastasis classification (P <.001 and P <.01, respectively) [5].
• A new stringent method of microarray analysis demonstrated that only four transcripts were nonspecifically affected by RNAi, whereas approximately 30 transcripts were affected in response to reduced VCP levels in a sequence-independent manner [29].
• Sequence analysis of the predicted polypeptide revealed 63 to 66% similarity with S. cerevisiae CDC 48p and its related genes in amphibians (p97ATPase) and mammals (Valosin Containing Protein, VCP), all possibly involved in the regulation of the cell cycle [30].

References