SASH1 Is a Scaffold Molecule in Endothelial TLR4 Signaling

Dauphinee, Shauna M.; Clayton, Ashley; Hussainkhel, Angela; Yang, Charlie; Park, Yoo-Jin; Fuller, Megan; Blonder, Josip; Veenstra, Timothy D.; Karsan, Aly

doi:10.4049/jimmunol.1200583

Cited by 54 publications

(52 citation statements)

References 47 publications

(59 reference statements)

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“…SASH1 has been reported to be a regulator of TRAF6 ubiquitination, and a de novo heterozygous variant in TRAF6 has recently been identified in patients with hypohydrotic ectodermal dysplasia. [25][26][27] TRAF6, initially identified as a regulator of NF-κB, also has an important role in tumorigenesis, invasion and metastasis, by modulating various signaling pathways. [28][29][30] Finally, because SASH1 has recently been reported as a scaffold molecule implicated in endothelial TLR4 signaling, which is implicated in innate immune responses, we wondered whether palmoplantar keratoderma and alopecia could be due to chronic fungal infection, but this hypothesis was ruled out.…”

Section: Discussionmentioning

confidence: 99%

“…[28][29][30] Finally, because SASH1 has recently been reported as a scaffold molecule implicated in endothelial TLR4 signaling, which is implicated in innate immune responses, we wondered whether palmoplantar keratoderma and alopecia could be due to chronic fungal infection, but this hypothesis was ruled out. 25 Dermatological diseases provide key examples of diseases with variants in the same gene that can either follow autosomaldominant or -recessive inheritance. For instance, anhidrotic ectodermal dysplasia is caused by EDAR and EDARADD variants which produce both recessive loss of function and dominant-negative effects.…”

Section: Discussionmentioning

confidence: 99%

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Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma

et al. 2014

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9SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor gene involved in the tumorigenesis of a spectrum of solid cancers. Heterozygous SASH1 variants are known to cause autosomal-dominant dyschromatosis. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous Moroccan family with two affected siblings presenting an unclassified phenotype associating an abnormal pigmentation pattern (hypo-and hyperpigmented macules of the trunk and face and areas of reticular hypo-and hyperpigmentation of the extremities), alopecia, palmoplantar keratoderma, ungueal dystrophy and recurrent spinocellular carcinoma. We identified a homozygous variant in SASH1 (c.1849G4A; p.Glu617Lys) in both affected individuals. Wound-healing assay showed that the patient's fibroblasts were better able than control fibroblasts to migrate. Following the identification of SASH1 heterozygous variants in dyschromatosis, we used reverse phenotyping to show that autosomal-recessive variants of this gene could be responsible for an overlapping but more complex phenotype that affected skin appendages. SASH1 should be added to the list of genes responsible for autosomal-dominant and -recessive genodermatosis, with no phenotype in heterozygous patients in the recessive form, and to the list of genes responsible for a predisposition to skin cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma

et al. 2014

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“…34,48,49 Recently, we and others have reported that ECs exposed to EndMT inducers, such as endotoxins and oxidative stress, are able to induce increased endothelial migration similar to that observed in myofibroblasts. [50][51][52] However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts and the underlying mechanism are not known.…”

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confidence: 99%

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

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During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-kB pathway. Oxidative stress induces the expression and secretion of TGF-b1 and TGF-b2 and p38 MAPK phosphorylation. Downregulation of TGF-b1 and TGF-b2 by siRNA technology abolished the H 2 O 2 -induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-b secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into myofibroblasts through a TGF-b-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.

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“…Both domains can mediate protein-protein interactions (13). However, the SAM domains can serve a more complex function in the way that they mediate protein-protein interactions through homologous and heterologous oligomerization with the SAM regions on other proteins (18). Meanwhile, the SAM domains can mediate binding between Smaug proteins and mRNAs to regulate transcription (13).…”

Section: Discussionmentioning

confidence: 99%

“…The SAM domain mediates protein-protein interactions through homologous and heterologous oligomerization with the SAM domains of other proteins, and it can mediate Smaug protein and mRNA binding to facilitate transcriptional regulation (16,17). SASH1 is a member of a recently described family of SH3/SAM adapter molecules according to its domain structure, thus suggesting a role in signaling pathways (18).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of SASH1 correlates with tumor progression and poor prognosis in ovarian carcinoma

et al. 2016

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Abstract. SAM-and SH3-domain containing 1 (SASH1) is a recently identified tumor suppressor gene that is required in the tumorigenesis of breast and other solid carcinomas. The SASH1 protein contains SH3 and SAM domains, indicating that it may serve an important role in intracellular signal transduction. The purpose of the present study was to investigate the expression of SASH1 in ovarian carcinoma and the correlation between its expression with clinical pathological features and clinical significance, and the effect of SASH1 on cell proliferation, apoptosis and migration of ovarian SKOV3 cells. The human ovarian carcinoma tissues and adjacent normal tissues were collected following surgery. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to detect the expression levels of SASH1 mRNA and protein, respectively. The expression levels of SASH1 mRNA and protein in ovarian carcinoma tissues were significantly lower than that observed in adjacent normal tissues (P<0.05). The expression levels of SASH1 in samples from patients without lymph nodes metastasis and patients with early FIGO stage was lower than those with lymph nodes metastasis and patients with advanced FIGO stage (P<0.05). Flow cytometry analysis and Transwell invasion chamber experiments were used to investigate the effect of SASH1 on the cell proliferation, apoptosis and migration of SKOV3 cells. The recombinant plasmid pcDNA3.1-SASH1 was constructed and transfected into SKOV3 cells. In addition, the SKOV3 cells in the pcDNA3.1-SASH1 group exhibited significantly reduced cell growth, proliferation, and migration ability compared to the empty vector group and normal group (P<0.01). There were a greater number of apoptotic cells in the pcDNA3.1-SASH1 group compared to the empty vector group and normal group (P<0.01). Taken together, these results indicated that SASH1 may be a tumor suppressor gene in ovarian carcinoma, and SASH1 expression inhibited growth, proliferation and migration, and enhanced apoptosis of SKOV3 cells.

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SASH1 Is a Scaffold Molecule in Endothelial TLR4 Signaling

Cited by 54 publications

References 47 publications

Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma

Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Downregulation of SASH1 correlates with tumor progression and poor prognosis in ovarian carcinoma

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