Molecular perspectives on p97–VCP: progress in understanding its structure and diverse biological functions

Wang, Qing; Song, Changcheng; Li, Chou-Chi H.

doi:10.1016/j.jsb.2003.11.014

Cited by 279 publications

(237 citation statements)

References 96 publications

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“…[1][2][3][4][5] Together with its co-factor Ufd1-Npl4, VCP extracts ubiquitylate substrates from the membrane for subsequent delivery to the proteasome during endoplasmic reticulum-associated degradation. 4 VCP and its other co-factor p47 are involved in fusion of endoplasmic reticulum, Golgi, and nuclear membrane.…”

Section: Discussionmentioning

confidence: 99%

“…The monoclonal antibody against VCP was purchased from Progen Biotechnik (Heidelberg, Germany), poly- 1 Plasmids containing mutation at Ϫ113 2 and both of Ϫ113 and Ϫ184 3 were sequentially generated and transfected to MCF7 (a), PC3 (b), and SW480 (c) cells. The luciferase activity showed a significant decrease with the transfection of the plasmid mutated at Ϫ113 and was completely lost with the transfection of the plasmid mutated at both Ϫ113 and Ϫ184.…”

Section: Antibodiesmentioning

confidence: 99%

“…[1][2][3][4][5] Notably, VCP is involved in activation of nuclear factor (NF)-B, a transcription factor promoting antiapoptosis, cell proliferation, and invasion. 6 VCP is abundant in all kinds of cells, accounting for more than 1% of total cellular protein.…”

mentioning

confidence: 99%

“…6 VCP is abundant in all kinds of cells, accounting for more than 1% of total cellular protein. 1 Recently, we showed that VCP is associated with metastatic potential of murine osteosarcoma cell line by using mRNA subtraction technique: the cell lines transfected with VCP showed the constant activation of NF-B, decreased apoptosis rates after stimulation with tumor necrosis factor (TNF)-␣, and increased metastatic potential. 7 Subsequent studies on the clinical samples showed that the high level of VCP expression in cancer cells correlated with the increase in recurrence rate and poor prognosis of patients with cancer of the liver, stomach, prostate, colorectum, pancreas, esophagus, and lung.…”

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confidence: 99%

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Pre-B-Cell Leukemia Transcription Factor 1 Regulates Expression of Valosin-Containing Protein, a Gene Involved in Cancer Growth

Qiu

Tomita

Zhang

et al. 2007

The American Journal of Pathology

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Valosin-containing protein (VCP) is involved in a wide variety of cellular functions. Our previous studies showed that the enhanced expression of VCP in cancer cells correlated with invasion and metastasis of cancers. Here, the regulatory mechanism for VCP transcription was investigated. Luciferase reporter constructs containing serially deleted 5 -flanking region of the VCP gene were transfected into MCF7 mammary carcinoma cell line, in which VCP was abundantly expressed. The deletion and mutation at the two binding motifs for pre-B-cell leukemia transcription factor 1 (PBX1) reduced the luciferase activity, indicating that these two PBX1 motifs medi- Valosin-containing protein (VCP, or p97), a member of the ATPases associated with various cellular activities (AAA) superfamily, is essential for a wide variety of cellular functions such as ubiquitin/proteasome-dependent protein degradation, membrane fusion, cell cycle regulation, and endoplasmic reticulum-associated degradation. 1-5 Notably, VCP is involved in activation of nuclear factor (NF)-B, a transcription factor promoting antiapoptosis, cell proliferation, and invasion. 6 VCP is abundant in all kinds of cells, accounting for more than 1% of total cellular protein. 1 Recently, we showed that VCP is associated with metastatic potential of murine osteosarcoma cell line by using mRNA subtraction technique: the cell lines transfected with VCP showed the constant activation of NF-B, decreased apoptosis rates after stimulation with tumor necrosis factor (TNF)-␣, and increased metastatic potential. 7 Subsequent studies on the clinical samples showed that the high level of VCP expression in cancer cells correlated with the increase in recurrence rate and poor prognosis of patients with cancer of the liver, stomach, prostate, colorectum, pancreas, esophagus, and lung. 8 -14 A clear correlation in VCP expression between mRNA and protein levels was found, indicating that the up-regulation of VCP transcription resulted in the enhanced VCP expression in cancers, which is advantageous for cancer cells to survive and metastasize. 8,10,13 This implies that VCP transcription would be a novel target for cancer therapy.Previous study on the basal transcription activity of mouse VCP gene revealed the importance of the 410-bp sequence of the 5Ј-flanking region, which contains consensus binding sites for several transcription factors. 15 However, the precise mechanism for VCP transcription has not been clarified yet. No study has been done on the human VCP promoter. In the present study, 5Ј-flanking DNA sequence of the VCP gene in the human genome was analyzed, revealing the pre-B-cell leukemia transcription factor 1 (PBX1) to be a key factor for transcription of VCP.

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Section: Discussionmentioning

confidence: 99%

Section: Antibodiesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Pre-B-Cell Leukemia Transcription Factor 1 Regulates Expression of Valosin-Containing Protein, a Gene Involved in Cancer Growth

Qiu

Tomita

Zhang

et al. 2007

The American Journal of Pathology

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“…VCP has been associated with several essential cell protein pathways 11 : cell cycle, homotypic membrane fusion, nuclear envelope reconstruction, postmitotic Golgi reassembly, DNA damage response, suppressor of apoptosis and ubiquitin-dependent protein degradation [12][13][14][15][16][17][18] . VCP also binds to expanded polyglutamine (poly-Q) protein aggregates 18,19 .…”

mentioning

confidence: 99%

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein

et al. 2004

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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. We investigated 13 families with IBMPFD linked to chromosome 9 using a candidate-gene approach. We found six missense mutations in the gene encoding valosincontaining protein (VCP, a member of the AAA-ATPase superfamily) exclusively in all 61 affected individuals. Haplotype analysis indicated that descent from two founders in two separate North American kindreds accounted for IBMPFD in ~50% of affected families. VCP is associated with a variety of cellular activities, including cell cycle control, membrane fusion and the ubiquitin-proteasome degradation pathway. 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.Hereditary inclusion body myopathy (IBM) associated with PDB and frontotemporal dementia (FTD), or IBMPFD, is a rare, complex and ultimately lethal autosomal dominant disorder (OMIM 605382; ref. 1). IBMPFD features adult-onset proximal and distal muscle weakness (clinically resembling limb girdle muscular dystrophy), early-onset PDB in most cases and 'premature' FTD 2 . Although the disorder was mapped to chromosome 9p21-p12, the genetic basis was not known.Within 13 families (12 from the United States and 1 from Canada, Fig. 1 and Supplementary Fig. 1 online), 82% of individuals had myopathy, 49% had PDB and 30% had early-onset FTD. The mean age of presentation was 42 years for both IBM and PDB, whereas FTD typically presented at age 53 years. In IBMPFD myopathic muscle and PDB osteoclasts, inclusions appear similar, suggestive of disruptions in the same pathological pathway.Haplotype analysis of the families with IBMPFD identified two ancestral, disease-associated haplotypes, distinguishing families 1, 3, 7 and 16 (group A) from families 2 and 5 (group B), both groups of Northern European ancestry ( Table 1

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Degradation of Misfolded Secretory and Membrane Proteins and Associated Diseases

Kim

Rao

2010

Encyclopedia of Life Sciences

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Proper folding and targeting of proteins are pivotal for the functioning of cells. Misfolded secretory and membrane proteins are selected for degradation by the proteasome, a multisubunit cytosolic protease. This disposal process termed endoplasmic reticulum‐associated degradation (ERAD) includes recognition of misfolded proteins in the endoplasmic reticulum (ER), retrotranslocation of substrates from the ER to the cytosol, ubiquitylation of substrates by the ubiquitylation enzymes, targeting of substrates to the proteasome, preprocessing of the substrates for efficient proteasomal degradation and final cleavage of misfolded proteins by the proteasome. Malfunctioning of ERAD components or accumulation of misfolded substrates has been found to cause various human diseases ranging from neurodegenerative disorders to cancers. Understanding the mechanism underlying ERAD provides a critical stepping‐stone to design drugs and develop preventative and therapeutic strategies against these diseases. Key Concepts: Misfolded secretory and membrane proteins are degraded by ERAD. Malfunctioning of ERAD components or accumulation of misfolded substrates cause various human diseases. ERAD is composed of multiple steps including substrates recognition, retrotranslocation, ubiquitylation, targeting of substrates to the proteasome and the cleavage of substrates by the proteasome. ERAD substrates are recognised and sorted into different degradation pathways based on the location of the misfolded domain and the topology of the protein. The retrotranslocation of the substrates from the ER to the cytosol is mediated by undefined channel proteins. Retrotranslocated substrates are ubiquitylated by membrane associated E3 enzymes with the help from E1, E2 enzymes. Postubiquitylation processes in ERAD include substrate extraction from the ER membrane, substrate delivery to the proteasome, preprocessing of the substrates and proteasomal degradation.

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Molecular perspectives on p97–VCP: progress in understanding its structure and diverse biological functions

Cited by 279 publications

References 96 publications

Pre-B-Cell Leukemia Transcription Factor 1 Regulates Expression of Valosin-Containing Protein, a Gene Involved in Cancer Growth

Pre-B-Cell Leukemia Transcription Factor 1 Regulates Expression of Valosin-Containing Protein, a Gene Involved in Cancer Growth

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein

Degradation of Misfolded Secretory and Membrane Proteins and Associated Diseases

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