Heat Shock Protein A4 Controls Cell Migration and Gastric Ulcer Healing

Sakurai, Toshiharu; Kashida, Hiroshi; Hagiwara, Satoru; Nishida, Naoshi; Watanabe, Tomohiro; Fujita, Jun; Kudo, Masatoshi

doi:10.1007/s10620-015-3561-8

Cited by 19 publications

(14 citation statements)

References 18 publications

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“…Interestingly, Zebrafish HspA4 was also upregulated in the intestinal epithelium within the gut under inflammatory stress conditions ( 169 ). Using HspA4-deficient mice and human tissue samples, Sakurai et al showed that the expression of HspA4 was inversely correlated to gastric ulcer healing induced by endoscopic submucosal resection ( 170 ). Further studies revealed that HspA4 downregulated the expression of stromal cell-derived factor 1 (SDF-1, also known as CXCL12), which signals through its cognate receptor CXC chemokine receptor 4 (CXCR4).…”

Section: Large Hsps and Inflammatory Diseasesmentioning

confidence: 99%

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Unfolding the Role of Large Heat Shock Proteins: New Insights and Therapeutic Implications

2016

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Heat shock proteins (HSPs) of eukaryotes are evolutionarily conserved molecules present in all the major intracellular organelles. They mainly function as molecular chaperones and participate in maintenance of protein homeostasis in physiological state and under stressful conditions. Despite their relative abundance, the large HSPs, i.e., Hsp110 and glucose-regulated protein 170 (Grp170), have received less attention compared to other conventional HSPs. These proteins are distantly related to the Hsp70 and belong to Hsp70 superfamily. Increased sizes of Hsp110 and Grp170, due to the presence of a loop structure, result in their exceptional capability in binding to polypeptide substrates or non-protein ligands, such as pathogen-associated molecules. These interactions that occur in the extracellular environment during tissue injury or microbial infection may lead to amplification of an immune response engaging both innate and adaptive immune components. Here, we review the current advances in understanding these large HSPs as molecular chaperones in proteostasis control and immune modulation as well as their therapeutic implications in treatment of cancer and neurodegeneration. Given their unique immunoregulatory activities, we also discuss the emerging evidence of their potential involvement in inflammatory and immune-related diseases.

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Section: Large Hsps and Inflammatory Diseasesmentioning

confidence: 99%

“…Further studies revealed that HspA4 downregulated the expression of stromal cell-derived factor 1 (SDF-1, also known as CXCL12), which signals through its cognate receptor CXC chemokine receptor 4 (CXCR4). The resultant inhibition of cell migration delayed gastric ulcer healing ( 170 ).…”

Section: Large Hsps and Inflammatory Diseasesmentioning

confidence: 99%

Unfolding the Role of Large Heat Shock Proteins: New Insights and Therapeutic Implications

2016

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“…The 110 kDa heat shock protein (Hsp110) family, including Hsp105, Apg1, and Apg2, are cytosolic chaperones that belong to the Hsp70 superfamily [ 6 – 10 ]. In addition to serving housekeeping roles during protein homeostasis, this protein family has been linked to wide ranging cellular processes including cell migration [ 11 ], spindle length control [ 12 ], and molecular scaffolding [ 13 ]. Importantly, as the Hsp110 family has also been implicated in many protein misfolding diseases, such as amyotrophic lateral sclerosis [ 14 , 15 ], prion disease [ 16 ], Alzheimer’s disease [ 17 ], cystic fibrosis [ 18 ], and polyglutamine disease [ 19 , 20 ], clarifying its precise mechanism of action in cells is paramount.…”

Section: Introductionmentioning

confidence: 99%

A Non-enveloped Virus Hijacks Host Disaggregation Machinery to Translocate across the Endoplasmic Reticulum Membrane

et al. 2015

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Mammalian cytosolic Hsp110 family, in concert with the Hsc70:J-protein complex, functions as a disaggregation machinery to rectify protein misfolding problems. Here we uncover a novel role of this machinery in driving membrane translocation during viral entry. The non-enveloped virus SV40 penetrates the endoplasmic reticulum (ER) membrane to reach the cytosol, a critical infection step. Combining biochemical, cell-based, and imaging approaches, we find that the Hsp110 family member Hsp105 associates with the ER membrane J-protein B14. Here Hsp105 cooperates with Hsc70 and extracts the membrane-penetrating SV40 into the cytosol, potentially by disassembling the membrane-embedded virus. Hence the energy provided by the Hsc70-dependent Hsp105 disaggregation machinery can be harnessed to catalyze a membrane translocation event.

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“…Real-time qPCR and immunohistochemistry were previously described [13][14][15][16] . The following antibodies were used: anti-Bmi1, anti-CD3, anti-CD20, and anti-CD68 (Dako, Santa Clara, CA, USA).…”

Section: Biochemical and Immunochemical Analysesmentioning

confidence: 99%

Clinical Significance of Bmi1 Expression in Inflammatory Bowel Disease

et al. 2017

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Background: Although the stem cell marker Bmi1 is overexpressed in many malignancies, its role in inflammation-associated cancer is unclear. Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and often results from refractory inflammatory bowel disease (IBD). Methods: To assess the involvement of Bmi1 in the development of CAC, we analyzed the gene expression of colon tissues collected from 111 patients with IBD and CAC. Results: In the colonic mucosa of patients with ulcerative colitis, the expression of Bmi1 correlated significantly with the expression of inflammatory cytokines such as IL-6, IL-17, IL-23, and tumor necrosis factor α (TNF-α). In the colonic mucosa of patients with Crohn's disease, the expression of Bmi1 correlated significantly with the expression of TNF-α and IL-23. The expression of Bmi1 was enhanced in the colonic mucosae of refractory IBD, suggesting that Bmi1 expression might be related to increased cancer risk. In addition, patients with high Bmi1 expression showed significantly lower response rates upon subsequent anti-TNF-α therapy as compared to patients with low Bmi1 expression. In human CAC specimens, the expression of Bmi1 was upregulated in nontumor tissues as well as tumors. Conclusions: Bmi1 expression is related to a refractory clinical course of IBD and upregulated in refractory IBD and CAC. Measurement of Bmi1 expression is a promising approach for the advanced treatment and personalized management of IBD patients.

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Heat Shock Protein A4 Controls Cell Migration and Gastric Ulcer Healing

Abstract: HSPA4 regulates the expression of SDF-1 and Twist in fibroblasts, thereby controlling gastric ulcer healing.

Cited by 19 publications

References 18 publications

Unfolding the Role of Large Heat Shock Proteins: New Insights and Therapeutic Implications

Unfolding the Role of Large Heat Shock Proteins: New Insights and Therapeutic Implications

A Non-enveloped Virus Hijacks Host Disaggregation Machinery to Translocate across the Endoplasmic Reticulum Membrane

Clinical Significance of Bmi1 Expression in Inflammatory Bowel Disease

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