Exploring the Smallest Active Fragment of HsQSOX1b and Finding a Highly Efficient Oxidative Engine

Zheng, Wenyun; Zhang, Wenyao; Hu, Wei; Zhang, Chao; Yang, Yi

doi:10.1371/journal.pone.0040935

Cited by 6 publications

(10 citation statements)

References 22 publications

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“…The retaining of the main functional domains of the protein and all of the redox-active disulfides in the isoforms QSOX1 c,d,e may preserve the main function of the enzyme - the oxidation of sulfhydryl groups to disulfides by reducing oxygen to hydrogen peroxide. This assumption is in agreement with the recently published functional studies of QSOX1 fragments which indicated the importance of interaction of the Trx and ERV/ALR domains for the thiol-oxidation activity of the QSOX1 protein [37], [38]. The products of the remaining splice variants ( QSOX1 f-i) lack all but the N-terminal fragment of the Trx1 domain and are most likely dysfunctional proteins.…”

Section: Discussionsupporting

confidence: 91%

“…Although initially identified as being strongly up-regulated in fibroblasts reaching confluence, it has also been since associated with growth factor activity, and it is highly expressed in cells with a large secretory load [12]. In different studies on QSOX1 a variety of functions have been ascribed to this enzyme including protection from apoptosis [11], [12], [39]–[42] and facilitation of tumour cells invasion [38]. Thus, the forced overexpression of quiescin 6 in human MCF-7 breast cancer cells rendered them more resistant to apoptosis arising from oxidative stress compared to control transfected cells, thereby implicating QSOX1 in cell survival [11] whilst the suppressed expression of quiescin in pancreatic cancer cell lines BxPC-3 and Panc-1 inhibited cancer cell invasion by activation of MMP-2 and MMP-9 Matrix Metalloproteinases [43].…”

Section: Discussionmentioning

confidence: 99%

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Elevated Transcription of the Gene QSOX1 Encoding Quiescin Q6 Sulfhydryl Oxidase 1 in Breast Cancer

et al. 2013

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The q arm of chromosome 1 is frequently amplified at the gene level in breast cancer. Since the significance of this is unclear we investigated whether 1q genes are overexpressed in this disease. The cDNA levels of 1q-located genes were analysed in a search for overexpressed genes. 26 genes mapping to the 1q arm show highly significant (P≤0.01) overexpression of transcripts in breast cancer compared to normal breast tissue. Amongst those showing the highest levels of overexpression in both expressed sequence tag (EST) and serial analysis of gene expression (SAGE) databases was enzyme quiescin Q6 sulfhydryl oxidase 1 (QSOX1). We investigated QSOX1 cDNA derived from T47D breast carcinoma cells by RT-PCR and 3′-RACE PCR and identified a novel extended form of QSOX1 transcript, containing a long 3′UTR, nearly double the size of the previously reported QSOX1 cDNA, and confirmed its 3′ end nucleotide sequence using RACE-PCR. We also used quantitative real-time PCR to analyse a panel of cDNAs derived from 50 clinically-graded normal and malignant breast tissue samples for the expression of QSOX1 mRNAs. QSOX1 transcription was elevated in an increasing proportion in the grade 2 and grade 3 tumours (graded according to the Nottingham prognostic index), with 10 of the 15 grade 3 tumours (67%) examined exceeding the normal range. There was a significant correlation between relative transcript level and clinical grade (P≤0.01) for all qPCR primer sets tested. QSOX1 mRNA levels, based on SAGE expression data, did not correlate with either Estrogen Receptor (ER) or Epidermal Growth Factor Receptor 2 (ErbB-2 or HER2/neu) expression. Our data indicate that QSOX1 is a potential new prognostic marker which may prove of use in the staging of breast tumours and the stratification of breast cancer patients.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Elevated Transcription of the Gene QSOX1 Encoding Quiescin Q6 Sulfhydryl Oxidase 1 in Breast Cancer

et al. 2013

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“…How ebselen inhibits QSOX1 through interaction with these residues is unclear because they are not thought to participate in the accepted disulfide relay mechanism. There is no evidence supporting cysteines other than the redox-active C-X-X-C motifs in the Trx1 and Erv domains as contributing to QSOX1 activity [ 11 , 18 , 32 – 34 ]. C237 is likely protonated and relatively inert to redox reactions since there are no nearby basic residues to stabilize a thiolate anion [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Ebselen inhibits QSOX1 enzymatic activity and suppresses invasion of pancreatic and renal cancer cell lines

et al. 2015

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Quiescin sulfhydryl oxidase 1 (QSOX1) is a highly conserved disulfide bond-generating enzyme that is overexpressed in diverse tumor types. Its enzymatic activity promotes the growth and invasion of tumor cells and alters extracellular matrix composition. In a nude mouse-human tumor xenograft model, tumors containing shRNA for QSOX1 grew significantly more slowly than controls, suggesting that QSOX1 supports a proliferative phenotype in vivo. High throughput screening experiments identified ebselen as an in vitro inhibitor of QSOX1 enzymatic activity. Ebselen treatment of pancreatic and renal cancer cell lines stalled tumor growth and inhibited invasion through Matrigel in vitro. Daily oral treatment with ebselen resulted in a 58% reduction in tumor growth in mice bearing human pancreatic tumor xenografts compared to controls. Mass spectrometric analysis of ebselen-treated QSOX1 mechanistically revealed that C165 and C237 of QSOX1 covalently bound to ebselen. This report details the anti-neoplastic properties of ebselen in pancreatic and renal cancer cell lines. The results here offer a “proof-of-principle” that enzymatic inhibition of QSOX1 may have clinical relevancy.

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“…The sulfhydral oxidase activity of rPbQSOX was determined at 25°C in 50 mM potassium phosphate buffer and 1 mM EDTA at pH 7.5 as described elsewhere (Raje et al, 2002 ; Zheng et al, 2012 ). The molar concentration of the enzyme was determined according to the molecular weight determined using the molar extinction coefficient from the ExPASy proteomics server ( http://www.expasy.org/ ).…”

Section: Methodsmentioning

confidence: 99%

Characterization of a Sulfhydryl Oxidase From Plasmodium berghei as a Target for Blocking Parasite Transmission

Zheng

Liu

et al. 2020

Front. Cell. Infect. Microbiol.

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Quiescin sulfhydryl oxidase (QSOX), present in a wide variety of eukaryotic species, catalyzes the insertion of disulfide bonds into unfolded, reduced proteins. Here we characterized the QSOX protein from the rodent malaria parasite Plasmodium berghei (PbQSOX), which is conserved in all sequenced malaria parasite species. The PbQSOX protein was not expressed in asexual erythrocytic stages, but was most abundantly expressed in ookinetes. Indirect immunofluorescence assays revealed PbQSOX was not only localized in cytoplasm of gametocytes, gametes and ookinetes, but also expressed on the surface of gametes and ookinetes. Western blot identified extracellular presence of PbQSOX in the culture medium of ookinetes suggestive of secretion. Pbqsox deletion (pbqsox) did not affect asexual intraerythrocytic development, but reduced exflagellation of male gametocytes as well as formation and maturation of ookinetes. Pbqsox deletion also led to a significant increase in the reduced thiol groups of ookinete surface proteins, suggesting that it may play a role in maintaining the integrity of disulfide bonds of surface proteins, which might be needed for ookinete development. Mosquitoes that fed on pbqsox-infected mice showed a significant reduction in ookinete and oocyst numbers compared to those fed on wild-type parasite-infected mice. Further, both polyclonal mouse antisera and a monoclonal antibody against the recombinant PbQSOX exhibited substantial transmission-blocking activities in in vitro and mosquito feeding assays, suggesting QSOX is a potential target for blocking parasite transmission.

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Exploring the Smallest Active Fragment of HsQSOX1b and Finding a Highly Efficient Oxidative Engine

Cited by 6 publications

References 22 publications

Elevated Transcription of the Gene QSOX1 Encoding Quiescin Q6 Sulfhydryl Oxidase 1 in Breast Cancer

Elevated Transcription of the Gene QSOX1 Encoding Quiescin Q6 Sulfhydryl Oxidase 1 in Breast Cancer

Ebselen inhibits QSOX1 enzymatic activity and suppresses invasion of pancreatic and renal cancer cell lines

Characterization of a Sulfhydryl Oxidase From Plasmodium berghei as a Target for Blocking Parasite Transmission

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