Construction and functional analysis of novel dominant-negative mutant of human SOX18 protein

Milivojevic, Milena; Petrović, Isidora; Kovacevic-Grujicic, Natasa; Popović, Jelena; Mojsin, Marija; Stevanović, Milena

doi:10.1134/s0006297913110096

Cited by 10 publications

(10 citation statements)

References 32 publications

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“…It has been observed that SOX18 takes part in wound healing processes and the development of atherosclerosis (19). Likewise, an increased level of this protein has been found in melanomas and malignant pancreatic, stomach and breast tumors (21).…”

Section: Introductionmentioning

confidence: 99%

Influence of miR-7a and miR-24-3p on the SOX18 transcript in lung adenocarcinoma

et al. 2017

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The molecular pathogenesis of the development of non-small cell lung carcinomas (NSCLCs) is extremely complex. Understanding the molecular basis of the development of this malignant tumor may enable the use of targeted therapy, which may result in a better treatment outome for these patients. Adenocarcinoma (AC) is the most common NSCLC subtype, equally common among smokers and non-smokers, and its pathogenesis remains unknown. The SOX18 protein is an important protein that plays a role in the development of blood and lymphatic vessels during the process of embryogenesis. Recent studies have also shown that the SOX18 protein may play a significant role in tumors, including lung cancers. In the present study, we analyzed the expression of the SOX18 protein and the mRNA level in postoperative samples of AC and non-malignant lung tissues (NMLTs), and a disparity in both levels was observed. Based on our previous observations that miR-7a and miR-24-3p are able to modulate SOX18 expression in NSCLC, the main aim of this study was to verify the miRNA modulation of the SOX18 transcript with the use of the MirTrap System in established lung cancer cell lines NCI-H1703, NCI-H522 and A549. The SOX18 mRNA expression level was significantly lower in AC than that noted in the NMLTs (P<0.0001). However, the protein levels were higher in AC cases compared to levels noted in the NMLTs (P<0.0001). Additionally, correlations between the RQ values of SOX18 in NMLT and AC cases (r=0.8195, P=0.0001), and between miR-7a and miR24-3p in AC cases (r=0.4344, P=0.0016), were noted. In conclusion, we confirmed that miR-7a and miR-24-3p are more highly expressed in NMLTs than in the AC samples, and that they modulate the SOX18 transcript in NSCLC cells.

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Section: Introductionmentioning

confidence: 99%

Influence of miR-7a and miR-24-3p on the SOX18 transcript in lung adenocarcinoma

et al. 2017

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“…The predicted truncated protein generated by the p.Gln181stop variant identified in this individual would disrupt the central TAD and also result in loss of the C‐terminal TAD. Functional studies of a truncated SOX18 protein that lacks the C‐terminal TAD retains its DNA binding capacity while having a dominant‐negative effect on its other protein binding properties (Milivojevic et al, ). We speculate the truncated protein predicted by the proband's nonsense variant would likely exert a similar dominant‐negative effect on SOX18 transcriptional activities, ultimately resulting in his phenotypic features.…”

Section: Discussionmentioning

confidence: 99%

A novel autosomal dominant mutation in SOX18 resulting in a fatal case of hypotrichosis–lymphedema–telangiectasia syndrome

Wangberg

Wigby

Jones

2018

American J of Med Genetics Pt A

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Hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) is a rare disorder caused by autosomal recessive and autosomal dominant mutations in SOX18. This gene encodes a transcription factor involved in the regulation and development of the human vasculature, lymphatic, and integumentary systems. Individuals with HLTS develop varying degrees of hypotrichosis, lymphedema, and telangiectasias. Other complications, such as renal failure and aortic dilation, have also been observed. Here, we report a neonate with a novel mutation in SOX18 (c.541C>T; p.Gln181stop) presenting with cardinal features of HLTS in addition to unique findings of severe chylothorax and relentless pulmonary hypertension that culminated in death. The purpose of this report is to summarize what is known about this evolving genetic syndrome and to speculate as to how mutations in SOX18 might produce the phenotype. K E Y W O R D S HLTS, hypotrichosis, lymphedema, pulmonary hypertension, SOX18, telangiectasia

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“…SiHa (ATCC, HTB-35) and Ca Ski (ATCC, CRL-1550) were maintained in Dulbecco's Modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS). Transfection experiments were carried out as previously described[ 23 , 24 ]. For co-transfection experiments, 10 μg of promoter reporter construct (892pCAT6) was co-transfected with 2 μg of either pcDNA4NLSMTGLI1, p4TO6MTGLI2 or pcDNA4/TO/GLI3 expression constructs[ 25 , 26 ].…”

Section: Methodsmentioning

confidence: 99%

“…For imunocytochemistryanalysis, cells were cultured in 24 well dishes and GLI1, GLI2 or GLI3 were co-transfected with pEGFP-C1 (Clontech Laboratories, Mountain View, CA, USA) in ratio 9:1 using Lipofectamine (Invitrogene, NY, USA). For functional analysis of SOX18 protein, cells were transfected as previously described[ 23 ].…”

Section: Methodsmentioning

confidence: 99%

“…Whole cell lysates (WCL) were prepared, proteins were separated and Western blot was performed as previously described[ 23 ]. Primary rabbit polyclonal antibodies against SOX18 (sc-20100; 1:1000) was purchased from Santa Cruz Biotechnology (Texas,USA), mouse monoclonal anti α-tubulin (CP06; 1:10000) was purchased from Calbiochem (Massachusetts, USA).…”

Section: Methodsmentioning

confidence: 99%

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SOX18 Is a Novel Target Gene of Hedgehog Signaling in Cervical Carcinoma Cell Lines

et al. 2015

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Although there is much evidence showing functional relationship between Hedgehog pathway, in particular Sonic hedgehog, and SOX transcription factors during embryonic development, scarce data are available regarding their crosstalk in cancer cells. SOX18 protein plays an important role in promoting tumor angiogenesis and therefore emerged as a promising potential target in antiangiogenic tumor therapy. Recently it became evident that expression of SOX18 gene in tumors is not restricted to endothelium of accompanying blood and lymphatic vessels, but in tumor cells as well.In this paper we have identified human SOX18 gene as a novel target gene of Hedgehog signaling in cervical carcinoma cell lines. We have presented data showing that expression of SOX18 gene is regulated by GLI1 and GLI2 transcription factors, final effectors of Hedgehog signaling, and that modulation of Hedgehog signaling activity in considerably influence SOX18 expression. We consider important that Hedgehog pathway inhibitors reduced SOX18 expression, thus showing, for the first time, possibility for manipulationwith SOX18 gene expression. In addition, we analyzed the role of SOX18 in malignant potential of cervical carcinoma cell line, and showed that its overexpression has no influence on cells proliferation and viability, but substantially promotes migration and invasion of cells in vitro. Pro-migratory effect of SOX18 suggests its role in promoting malignant spreading, possibly in response to Hedgehog activation.

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Construction and functional analysis of novel dominant-negative mutant of human SOX18 protein

Cited by 10 publications

References 32 publications

Influence of miR-7a and miR-24-3p on the SOX18 transcript in lung adenocarcinoma

Influence of miR-7a and miR-24-3p on the SOX18 transcript in lung adenocarcinoma

A novel autosomal dominant mutation in SOX18 resulting in a fatal case of hypotrichosis–lymphedema–telangiectasia syndrome

SOX18 Is a Novel Target Gene of Hedgehog Signaling in Cervical Carcinoma Cell Lines

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