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: 4.6). 02/2007; 170(1):152-9. DOI: 10.2353/ajpath.2007.060722
Source: PubMed

ABSTRACT 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 · 2.26 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. DOI:10.1016/j.canlet.2013.05.030 · 5.02 Impact Factor
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    • "The PBX2 expression is correlated with VCP expression, which has been revealed in NSCLC cell lines and in the clinical samples. It has been shown that PBX enhanced the promoter activity of VCP gene through their recognition sites (Qiu et al., 2007). The PBX-VCP pathway may play an important role in regulating differentiation and proliferation of tumor cells (Qiu et al., 2009). "
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    ABSTRACT: In this study, we investigated the interrelationship between clinicopathologic findings and pre-B-cell leukemia transcription factor 2 (PBX2) expression in gingival squamous cell carcinoma (GSCC). Expression level of PBX2 was immunohistochemically examined in 66 GSCC subjects (30 men and 36 women) with ages ranging from 42 to 85 (median 64.5) years, in which staining intensity in tumor cells was categorized as either weaker (level 1) or equal to/stronger (level 2) than that in the endothelial cells. ResULTS: PBX2 expression is correlated with valosin-containing protein (VCP) expression. Univariate and multivariate analyses revealed a high level of PBX2 expression to be a poor prognosticator for disease-free survival (DFS) and overall survival (OS), and PBX2 expression was an independent prognostic factor for both DFS and OS in GSCC. PBX2 expression level in GSCC is prognostic. PBX2 may be a useful marker to identify the potential for progression in GSCC.
    Journal of Zhejiang University SCIENCE B 03/2012; 13(3):168-75. DOI:10.1631/jzus.B1100077 · 1.29 Impact Factor
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