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

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 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.

Interaction between Salt-inducible Kinase 2 (SIK2) and p97/Valosin-containing Protein (VCP) Regulates Endoplasmic Reticulum (ER)-associated Protein Degradation in Mammalian Cells

“…The current results, demonstrating that the interaction between SIK2 and p97/VCP regulates ERAD, supports the possibility that SIK2, like p97/VCP, may serve as a key regulator in the ubiquitin-proteasome system and autophagy. Furthermore, this regulatory network may have significant implications in cancer biology as previous reports have shown that elevated p97/VCP levels correlate with metastasis of several types of cancers (55)(56)(57)(58) and that SIK2 is required for cancer cell growth (9). Collectively, these observations strengthen the notion that SIK2 is necessary for the proper functions and integrity of the ubiquitin-proteasome system and autophagy, which in turn are critical for cancer cell proliferation and survival.…”

Microarray and proteomics expression profiling identifies several candidates, including the valosin‐containing protein (VCP), involved in regulating high cellular growth rate in production CHO cell lines

“…While VCP has been shown to be involved in a wide variety of cellular processes, including transcriptional regulation, membrane fusion, cellcycle control and cell growth (reviewed in Wang et al, 2004), the detailed mechanisms of VCP function have yet to be fully elucidated. VCP expression has been correlated with high disease recurrence rate and poor prognosis in several cancers (Tsujimoto et al, 2004;Yamamoto et al, 2004Yamamoto et al, , 2005 and it has been shown to play an important role in invasion and metastasis of cancer cells via its activation and regulation of the NF-kB (Asai et al, 2002;Dai et al, 1998;Qiu et al, 2007;Zhang et al, 2007), a transcription factor involved in apoptosis, invasion and cell proliferation. Several recent studies have shown that VCP is a coimmunoprecipitated target of Activated serine-threonine kinase (Akt), which phosphorylates VCP (Livingstone et al, 2005;Vandermoere et al, 2006) and is required for cell survival (Klein et al, 2005;Vandermoere et al, 2006Vandermoere et al, , 2007.…”

VCP mutations are not a major cause of familial amyotrophic lateral sclerosis in the UK

“…As most pathogenic mutations in VCP that have been detected in IBMPFD and ALS are found in the N-terminal domain, the L1 linker and the D1/ATPase domain ( Fig. 1a), we screened ten exons [1][2][3][5][6][7]10,13,14,17] harbouring most known mutations found in ALS and IBMPFD together with 5′UTR and 3′UTR regions of the gene that have not been extensively studied before. The FALS cohort consisted of 102 index cases, from which known mutations in SOD1, VAPB, TARDBP, FUS and DAO genes had been previously excluded.…”