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

Department of Pathology, Medical School of Tongji University, Shanghai, China.
American Journal Of Pathology (Impact Factor: 4.59). 02/2007; 170(1):152-9. DOI: 10.2353/ajpath.2007.060722
Source: PubMed


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 mediated the transactivation of the VCP gene. Chromatin immunoprecipitation assay showed the binding of PBX-1 to the 5'-flanking region of the VCP gene. The knockdown of PBX1 by siRNA decreased the expression level of VCP. VCP is reported to maintain cell viability after the treatment of tumor necrosis factor-alpha. The viability of tumor necrosis factor-alpha-treated cells was significantly reduced in PBX1 knockdown MCF7. These findings indicate that PBX1 plays a crucial role in VCP expression and function and that the PBX-VCP pathway might be important for cell survival under cytokine stress.

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    • "Functionally, the consequences of impaired transcription of VCP would affect the export of ubiquitinated proteins from the endoplasmic reticulum to the proteasome for degradation, which could contribute to the build-up of the ubiquitinated protein inclusions, an established hallmark of ALS. In addition , the c.-360G N C variant is located within a predicted transcription factor binding site for MAZ [13] (Fig. 1c). Clearance of existing ubiquitinated aggregates may similarly be impaired as a consequence of decreased levels of VCP expression [14]. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing loss of motor neurons in the spinal cord, brain stem and cerebral cortex. Mutations in the Valosin containing protein (VCP) gene have recently been identified in Familial ALS (FALS) patients, accounting for ~1% of all FALS cases. In order to study the frequency of VCP mutations in UK FALS patients, we have screened the exons known to harbour mutations together with 3' and 5' UTR sequences. No coding changes were identified in this UK cohort and no common polymorphisms were associated with FALS. However, we identified an imperfect hexanucleotide expansion (8 repeats), c.-221_-220insCTGCCACTGCCACTGCCG, in the 5'UTR of a FALS case and a 7-repeat hexanucleotide repeat in a Sporadic ALS case (SALS) that were not present in 219 UK controls. Subsequent screening of sequence data from 1844 controls (1000 genomes Phase 3) revealed the presence of the 7-repeat (0.3%) and a single individual with an 8-repeat containing a homogeneous insert [CTGCCG]3 but no individuals with the heterogeneous insert found in FALS ([CTGCCA]2[CTGCCG]). Two novel single base pair substitutions, c.-360G>C and c.2421+94C>T, were found in FALS cases in the 5' and 3' UTRs respectively. The hexanucleotide expansion and c.-360G>C were predicted to be pathogenic and were found in FALS cases harbouring C9orf72 expansions. The SALS case with a 7 repeat lacked a C9orf72 expansion. We conclude that VCP mutations are not a major cause of FALS in the UK population although novel rare variations in the 5' UTR of the VCP gene may be pathogenic. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of the Neurological Sciences 01/2015; 349(1-2). DOI:10.1016/j.jns.2015.01.021 · 2.47 Impact Factor
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    • "The binding of ELF2 to this motif has been shown by ChIP assay [101]. Since knock-down of these factors reduced both p97/CDC-48 levels and cell viability thereby increasing the susceptibility of the cells to undergo apoptosis, these factors may play an important role in the regulation of p97/CDC-48-mediated cell survival [62] [101]. PBX2 has been identified as a highly related homolog to PBX1 [51]. "
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    ABSTRACT: P97/CDC-48 is a prominent member of a highly evolutionary conserved Walker cassette - containing AAA+ ATPases. It has been involved in numerous cellular processes ranging from the control of protein homeostasis to membrane trafficking through the intervention of specific accessory proteins. Expression of p97/CDC-48 in cancers has been correlated with tumor aggressiveness and prognosis, however the precise underlying molecular mechanisms remain to be characterized. Moreover p97/CDC-48 inhibitors were developed and are currently under intense investigation as anticancer drugs. Herein, we discuss the role of p97/CDC-48 in cancer development and its therapeutic potential in tumor cell biology.
    Cancer letters 05/2013; 337(1). DOI:10.1016/j.canlet.2013.05.030 · 5.62 Impact Factor
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    • "In addition, VCP has been shown to associate physically with ubiquitinated IκBα and to target IκBα to the proteasome for degradation [7], [8]. It was reported that pre-B-cell leukemia transcription factor 1(PBX1) regulates expression of VCP [9]. But so far there is no report about the post-transcriptional regulation of the VCP expression. "
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    ABSTRACT: Valosin containing protein (VCP)/p97 plays various important roles in cells. Moreover, elevated expression of VCP in hepatocellular carcinoma (HCC) is correlated with increased incidence of recurrence. But the role of VCP in HCC progression in vitro and in vivo is unclear. And there are few reports about the regulation mechanism on the expression of VCP in HCC. In this study, it was identified that the level of VCP was frequently increased in human HCC tissues. In addition, down-regulation of VCP with siRNAs could dramatically suppress the genesis and progression of tumor in vivo. It was found that miR-129-5p directly inhibited the expression of VCP in several HCC cell lines. Meanwhile, the level of VCP in HCC tissues was negatively associated with the level of miR-129-5p. Our further investigation showed that the enhanced expression of miR-129-5p also suppressed tumor growth in vivo. Moreover, it was revealed that miR-129-5p could inhibit the degradation of IκBα and increase the apoptosis and reduce the migration of HCC cells by suppressing the expression of VCP. Our results revealed that the expression of VCP was directly regulated by miR-129-5p and this regulation played an important role in the progression of HCC.
    PLoS ONE 04/2012; 7(4):e35800. DOI:10.1371/journal.pone.0035800 · 3.23 Impact Factor
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