Identification of a Crucial Site for Synoviolin Expression

Tsuchimochi, Kaneyuki; Yagishita, Naoko; Yamasaki, Satoshi; Amano, Tetsuya; Kato, Y.; Kikuchi, Kôichi; Aratani, Satoko; Fujita, Hidetoshi; Ji, Fengyun; Sugiura, Akiko; Izumi, Toshihiko; Sugamiya, Asako; Maruyama, Ikuro; Fukamizu, Akiyoshi; Komiya, Setsuro; Nishioka, Kusuki; Nakajima, Takeshi

doi:10.1128/mcb.25.16.7344-7356.2005

Cited by 25 publications

(34 citation statements)

References 63 publications

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“…3). In addition, our recent analyses of the synoviolin promoter also demonstrated that transcriptional regulation of the gene is critical for cell growth and apoptosis in vitro (10), which strongly suggests that the amount of Synoviolin is critical to the regulation of synovial cell overgrowth.…”

Section: Discussionmentioning

confidence: 99%

Resistance to endoplasmic reticulum stress is an acquired cellular characteristic of rheumatoid synovial cells

Yamasaki

Yagishita²,

Tsuchimochi³

et al. 2006

Int J Mol Med

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Abstract.Synoviolin is an endoplasmic reticulum (ER)-resident E3 ubiquitin ligase which plays a critical role in ERassociated degradation (ERAD). We found that Synoviolin is a novel causative factor for rheumatoid arthritis (RA), which is especially up-regulated in proliferating synovial cells in the disease. We attempted to examine the role of Synoviolin in ER stress-induced apoptosis and proliferation of synovial cells. RA synovial cells (RSCs) were refractory to ER stressinduced apoptosis compared with HEK293 or HeLa cells. RSCs were also more resistant to the apoptosis than synovial cells from osteoarthritis patients, significantly. Down-regulation of Synoviolin by siRNA increased the susceptibility to ER stress-induced apoptosis in RSCs. Knock-down of Synoviolin by siRNA did not only induce apoptosis of RSCs but also inhibited their proliferation in vitro. These data suggest that RSCs are extraordinarily refractory to ER stress-induced apoptosis, and we termed this special property 'hyper-ERAD'. Since Synoviolin is overexpressed in RSCs, and is known to play a critical role in the ERAD system as E3 ubiquitin ligase, hyper-ERAD is likely to present in these cells. Subsequently, the hyper-ERAD may cause synovial hyperplasia through its anti-apoptotic effect in RA. Further analyses are necessary to address this point, however, resistance to ER stress-induced apoptosis, or hyper-ERAD is a noteworthy new cellular characteristic of RSCs.

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Section: Discussionmentioning

confidence: 99%

Resistance to endoplasmic reticulum stress is an acquired cellular characteristic of rheumatoid synovial cells

Yamasaki

Yagishita²,

Tsuchimochi³

et al. 2006

Int J Mol Med

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“…Genes located near these loci perform a broad range of functions including DNA synthesis and repair (REV3L [48] and PCNA [73]), transcription (XPMC2H [55], HNRPUL1 [45], BANP [67], ATF7 [64], ZNF215 [3], and MYC [21]), mitochondrial function (CA5A [58] and COX7A2L [79]), and mitotic spindle assembly (CDCA8) (16). One target has direct involvement in the secretory functions of the cell (COH1) (41), while another target has a direct link to the unfolded protein response (UPR) (SYVN1) (75). CGI ChIP-chip to identify p53 targets genes therefore identifies a broad range of potential target genes that may mediate direct effects on p53 function.…”

Section: Resultsmentioning

confidence: 99%

Functional Analysis of p53 Binding under Differential Stresses

Krieg

Hammond

Giaccia

2006

Molecular and Cellular Biology

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Hypoxia and DNA damage stabilize the p53 protein, but the subsequent effect that each stress has on transcriptional regulation of known p53 target genes is variable. We have used chromatin immunoprecipitation followed by CpG island (CGI) microarray hybridization to identify promoters bound by p53 under both DNA-damaging and non-DNA-damaging conditions in HCT116 cells. Using gene-specific PCR analysis, we have verified an association with CGIs of the highest enrichment (>2.5-fold) (REV3L, XPMC2H, HNRPUL1, TOR1AIP1, glutathione peroxidase 1, and SCFD2), with CGIs of intermediate enrichment (>2.2-fold) (COX7A2L, SYVN1, and JAG2), and with CGIs of low enrichment (>2.0-fold) (MYC and PCNA). We found little difference in promoter binding when p53 is stabilized by these two distinctly different stresses. However, expression of these genes varies a great deal: while a few genes exhibit classical induction with adriamycin, the majority of the genes are unchanged or are mildly repressed by either hypoxia or adriamycin. Further analysis using p53 mutated in the core DNA binding domain revealed that the interaction of p53 with CGIs may be occurring through both sequence-dependent and -independent mechanisms. Taken together, these experiments describe the identification of novel p53 target genes and the subsequent discovery of distinctly different expression phenomena for p53 target genes under different stress scenarios.The tumor microenvironment is a major factor influencing tumor growth, metastatic potential, and response to chemotherapeutic drugs and radiation therapy (7). The hypoxia-inducible factor (HIF) family of transcription factors regulates the expression of key enzymes in anaerobic glycolysis and proangiogenic factors (i.e., vascular endothelial growth factor), aiding cells in adapting to a low-oxygen environment (15). Thus, a tumor adapts to hypoxia first by sustaining itself via anaerobic metabolism and then by stimulating angiogenesis to acquire more nutrients and oxygen. However, the resulting vasculature tends to have aberrant structures with irregular blood flow and leaky walls, paradoxically creating regions of transient hypoxia and reoxygenation (76). Reoxygenation after hypoxia causes DNA damage, exacerbating genomic instability (25). The porous structure of the tumor vasculature may also provide an escape route for metastasizing cells. Repeated cycles of hypoxia, vascular formation, and reoxygenation select for cells that are more likely to survive in a restrictive environment. The consequences of this process are cancer cells that are more aggressive, more likely to metastasize, and more likely to be resistant to radiation and chemotherapy. Intimately tied to this process is the selection for cells that have lost the expression of functional p53 (19).A variety of cellular stresses, including DNA damage, oncogenic transformation, and hypoxia, stabilize the p53 protein by activating a host of stress-inducible kinases that phosphorylate p53 and MDM2, resulting in increased levels of p53 (17). Stabilized ...

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“…The Ets binding site (EBS) is determined to be the crucial site for synoviolin transcription in vivo and in vitro, and GABP, a transcription factor known to be down stream of MAP kinases such as JNK and ERK, is proved to be bind to it. 51 The MAP kinase signals are activated in both neoplasm and RA, thus these signal may induce constitutively high expression of Synoviolin in these diseases. 52,53 Similar pathogenic mechanism for neoplasm progression has been actually implicated in a human disease.…”

Section: Impact Of Synoviolin Dysregulationmentioning

confidence: 99%