Analysis of Novel Disease-Related Genes in Bronchial Asthma

Yuyama, Noriko; Davies, Donna E.; Akaiwa, Mina; Matsui, Kazuaki; Hamasaki, Yuhei; Suminami, Yoshinori; Yoshida, Ning Lu; Maeda, Miyako; Pandit, Anita; Lordan, James; Kamogawa, Yumiko; Arima, Kazuhiko; Nagumo, Fumio; Sugimachi, Mitsuhiko; Berger, Anna Maria Busse; Richards, Ivan M.; Roberds, Steven L.; Yamashita, Tetsuji; Kishi, Fumio; Katô, Hiroshi; Arai, Kohei; Ohshima, Koichi; Tadano, Jutaro; Hamasaki, Naotaka; Miyatake, Shoichiro; Sugita, Yuji; Holgate, Stephen T.; Izuhara, Kenji

doi:10.1006/cyto.2002.1972

Cited by 175 publications

(112 citation statements)

References 30 publications

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“…We further demonstrated that SCCA1, but not SCCA2, potently inhibits the cysteine protease activities of protozoa-or helminth-derived cysteine proteases such as CPB2.8 from Leishmania mexicana, cruzain from Trypanosoma cruzi, rhodesain from Trypanosoma brucei rhodesience, and cathepsin L2 from Fasciola hepatica, indicating that secretory SCCA1 may act as a defense mechanism against parasite development. This finding is consistent with the notion that IL-4 and IL-13 play critical and redundant roles in the defense against gastrointestinal nematodes [99] and with the results that SCCA1/ SCCA2 are downstream molecules in human bronchial epithelial cells and keratinocytes [100,101]. Katagiri et al have shown that upon exposure of keratinocytes to ultraviolet (UV), SCCA1 translocates to the nucleus and is bound to phosphorylated JNK1, alleviating its kinase activity [102] (Fig.…”

Section: Maspin (Serpin B5)supporting

confidence: 90%

Recent progress in understanding the diversity of the human ov-serpin/clade B serpin family

Izuhara

Ohta

Kanaji

et al. 2008

Cell. Mol. Life Sci.

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The inhibitory mechanism against proteases is important in the maintenance of homeostasis or health in the body. The human ovalbumin serpin (ov-serpin)/clade B serpin family is one group of the human serpins, a family of serine protease inhibitors. They have acquired diversity in the profiles of target proteases, inhibitory mechanisms, and localization patterns during their evolution. Most serpins target serine proteases, however, some ov-serpins target only cysteine proteases or both serine and cysteine proteases and furthermore, several ov-serpins do not possess inhibitory activities. Although the ov-serpins act primarily as intracellular serpins, some show extracellular and nuclear localizations. Such diversity enables the ov-serpins to play multiple physiological roles in the body. Recent analyses have revealed that the functions of human ov-serpins are more diversified than we previously knew. In this article, we describe recent progress in our understanding of how the human ov-serpin/clade B serpin family demonstrates diversity.

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Section: Maspin (Serpin B5)supporting

confidence: 90%

Recent progress in understanding the diversity of the human ov-serpin/clade B serpin family

Izuhara

Ohta

Kanaji

et al. 2008

Cell. Mol. Life Sci.

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“…As a result, the human ␣2(I) collagen gene showed the highest induction by IL-13 (5.96-fold). Previous studies on the target genes of IL-13 by the cDNA microarray analysis showed that tenascin-C, collagen IV, and the biglycan gene are induced by IL-13 in human bronchial epithelial cells (28,29). These studies suggest that IL-13 is one of the profibrogenic cytokines.…”

Section: Il-13 Induces Type I Collagen Genementioning

confidence: 76%

Interleukin-13 Stimulates the Transcription of the Human α2(I) Collagen Gene in Human Dermal Fibroblasts

Jinnin¹,

Ihn²,

Yamane

et al. 2004

Journal of Biological Chemistry

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Interleukin (IL)-13 is a novel lymphokine produced by activated Type 2 helper cells. In this study, we examined the target genes of IL-13 by the cDNA microarray analysis in human dermal fibroblasts. We focused on the human ␣2(I) collagen gene, which was one of the IL-13-induced genes by the microarray analysis. IL-13 induced type I collagen protein as well as mRNA in a dose-dependent manner. Actinomycin D, an RNA synthesis inhibitor, significantly blocked the IL-13-mediated up-regulation of ␣2(I) collagen mRNA expression, whereas cycloheximide, a protein synthesis inhibitor, did not block this up-regulation. In addition, IL-13 treatment induced the promoter activity of ␣2(I) collagen by nuclear run-on transcription assay and chloramphenicol acetyltransferase assay. IL-13-mediated transcriptional activation of ␣2(I) collagen gene or type I collagen protein up-regulation was inhibited by the treatment of fibroblasts with a selective phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, or STAT6 antisense oligonucleotide, but not by PD98059, a specific inhibitor of MEK/ERK, or SB202190 or SB203580, specific inhibitors of p38 MAPK; IL-13 induced the phosphorylation of PI3K p85 regulatory subunit and STAT6. These results suggest that IL-13 may play a role in the regulation of extracellular matrix and indicate the possible therapeutic value of the blockade of IL-13 signaling pathways via PI3K and STAT6 in fibrosis.

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“…Although we are unaware of any natural mutation of a clade B serpin that leads to a disease phenotype in humans at this time, these SNPs are likely to contribute to quantitative traits, such as chronic obstructive pulmonary disease and asthma (55,56). With the advent of SNP genotyping, this hypothesis is readily testable and might identify a clade B serpin haplotype associated with disorders manifested by significant alterations in peptidase-inhibitor imbalance.…”

Section: Discussionmentioning

confidence: 99%

SERPINB11 Is a New Noninhibitory Intracellular Serpin

Askew

Çataltepe

Kumar

et al. 2007

Journal of Biological Chemistry

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SERPINB11, the last of 13 human clade B serpins to be described, gave rise to seven different isoforms. One cDNA contained a premature termination codon, two contained splice variants, and four contained full-length open reading frames punctuated by eight single nucleotide polymorphisms (SNPs). The SNPs encoded amino acid variants located within the serpin scaffold but not the reactive site loop (RSL). Although the mouse orthologue, Serpinb11, could inhibit trypsin-like peptidases, SERPINB11 showed no inhibitory activity. To determine whether the human RSL targeted a different class of peptidases or the serpin scaffold was unable to support inhibitory activity, we synthesized chimeric human and mouse proteins, in which the RSLs had been swapped. The human RSL served as a trypsin inhibitor when supported by mouse scaffold sequences. Conversely, the mouse RSL on the human scaffold showed no inhibitory activity. These findings suggested that variant residues in the SERPINB11 scaffold impaired serpin function. SDS-PAGE analysis supported this notion as RSL-cleaved SERPINB11 was unable to undergo the stressed-to-relaxed transition typical of inhibitory type serpins. Mutagenesis studies supported this hypothesis, since the reversion of amino acid sequences in helices D and I to those conserved in other clade B serpins partially restored the ability of SERPINB11 to form covalent complexes with trypsin. Taken together, these findings suggested that SER-PINB11 SNPs encoded amino acids in the scaffold that impaired RSL mobility, and HapMap data showed that the majority of genomes in different human populations harbored these noninhibitory SERPINB11 alleles. Like several other serpin superfamily members, SERPINB11 has lost inhibitory activity and may have evolved a noninhibitory function.Serpins are a superfamily of serine and cysteine peptidase inhibitors that contain ϳ1500 family members and are found in all domains of life (Eukarya, Eubacteria, and Archaea) as well as many Poxviridae (reviewed in Refs. 1-4). Unlike canonical inhibitors, inhibitory serpins employ a unique suicide substrate-like inhibitory mechanism to neutralize their target peptidases. The surface-exposed reactive site loop (RSL) 4 serves as a pseudosubstrate and binds to the active site of the peptidase. Upon cleavage of the RSL, the metastable serpin molecule undergoes a major conformational rearrangement and traps the covalently attached peptidase in a distorted, inactive form (5). A small proportion of serpins are noninhibitory and aid in diverse functions, such as hormone transport (e.g. SERPINA7/ thyroxine binding globulin) and protein folding (e.g. SER-PINH1/HSP47) (6, 7).Serpins are classified into 17 clades based on phylogenetic relationships (8). So far, 36 human serpins from nine clades (A-I) have been identified (2). The majority of serpins are plasma proteins that serve as critical regulators of important physiological processes, such as blood coagulation, fibrinolysis, and inflammation. In contrast, clade B serpins exist predominantly, but...

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Analysis of Novel Disease-Related Genes in Bronchial Asthma

Cited by 175 publications

References 30 publications

Recent progress in understanding the diversity of the human ov-serpin/clade B serpin family

Recent progress in understanding the diversity of the human ov-serpin/clade B serpin family

Interleukin-13 Stimulates the Transcription of the Human α2(I) Collagen Gene in Human Dermal Fibroblasts

SERPINB11 Is a New Noninhibitory Intracellular Serpin

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