Identification of IGFBP-6 as an effector of the tumor suppressor activity of SEMA3B

Koyama, Nobuyuki; Zhang, J; Huqun,; Miyazawa, Hitoshi; Tanaka, Tomoaki; Su, Xiaotian; Hagiwara, Koichi

doi:10.1038/onc.2008.263

Cited by 22 publications

(19 citation statements)

References 40 publications

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“…Approximately 35% of the discovered gene sets (165/423 sets) were enriched in both full-length Myb and ∆N Myb expressing cells ( Figure 6B), this included many of the top-ranking gene sets (categories denoted with gray in the side bar, Figure 6A) [40]. Furthermore, full-length Myb and ∆N Myb both activated genes that are overrepresented in a previously published c-Myb target gene list (LIU_CMYB_TARGETS_UP) [36] and silenced genes associated with SEMA3B expression (KOYAMA_SEMA3B_TARGETS_UP, Figure 6A) [41]. Thus, our enrichment results are consistent with previously published findings and our own findings that ∆N Myb and full-length Myb commonly regulated some genes.…”

Section: ∆N Myb Uniquely Modulates Gene Sets Implicated In Neuronal Cmentioning

confidence: 75%

N-Terminal Truncated Myb with New Transcriptional Activity Produced Through Use of an Alternative MYB Promoter in Salivary Gland Adenoid Cystic Carcinoma

Frerich

Sedam

Kang

et al. 2019

Cancers

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Adenoid cystic carcinoma (ACC) is an aggressive salivary gland tumor that frequently displays perineural invasion and is often associated with translocations or overexpression of the MYB oncogene. Detailed analyses of MYB transcripts from ACC patient samples revealed that ACC tumors utilize an alternative MYB promoter, which is rarely used in normal cells or other tumor types. The alternative promoter transcripts produce N-terminally truncated Myb proteins lacking a highly conserved and phosphorylated domain, which includes the pS11 epitope that is frequently used to detect Myb proteins. In RNA-seq assays, Myb isoforms lacking the N-terminal domain displayed unique transcriptional activities, regulating many genes differently than full-length Myb. Thus, a regulatory pathway unique to ACC activates the alternative MYB promoter, leading to the production of a truncated Myb protein with altered transcriptional activities. This could provide new therapeutic opportunities for ACC patients.

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Section: ∆N Myb Uniquely Modulates Gene Sets Implicated In Neuronal Cmentioning

confidence: 75%

N-Terminal Truncated Myb with New Transcriptional Activity Produced Through Use of an Alternative MYB Promoter in Salivary Gland Adenoid Cystic Carcinoma

Frerich

Sedam

Kang

et al. 2019

Cancers

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“…IGFBP4, IGFBP6 are O-glycosylated and IGFBP5 and IGFBP6 are N-glycosylated [49,50]. IGFBP6 is tumor suppressor, [51] extracellular protein [52] and preferentially binds to IGF-II [53]. IGFBP2 serves as an antiapoptotic biomarker [54].…”

Section: Resultsmentioning

confidence: 99%

Proteomic analysis of human vitreous humor

et al. 2014

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BackgroundThe vitreous humor is a transparent, gelatinous mass whose main constituent is water. It plays an important role in providing metabolic nutrient requirements of the lens, coordinating eye growth and providing support to the retina. It is in close proximity to the retina and reflects many of the changes occurring in this tissue. The biochemical changes occurring in the vitreous could provide a better understanding about the pathophysiological processes that occur in vitreoretinopathy. In this study, we investigated the proteome of normal human vitreous humor using high resolution Fourier transform mass spectrometry.ResultsThe vitreous humor was subjected to multiple fractionation techniques followed by LC-MS/MS analysis. We identified 1,205 proteins, 682 of which have not been described previously in the vitreous humor. Most proteins were localized to the extracellular space (24%), cytoplasm (20%) or plasma membrane (14%). Classification based on molecular function showed that 27% had catalytic activity, 10% structural activity, 10% binding activity, 4% cell and 4% transporter activity. Categorization for biological processes showed 28% participate in metabolism, 20% in cell communication and 13% in cell growth. The data have been deposited to the ProteomeXchange with identifier PXD000957.ConclusionThis large catalog of vitreous proteins should facilitate biomedical research into pathological conditions of the eye including diabetic retinopathy, retinal detachment and cataract.

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“…IGFBP‐6 has been recently reported to interact with Ku80, a DNA‐end binding protein, in the cytoplasm to regulate cell survival, and this effect may be IGF‐dependent 31. IGFBP‐6 acts as an effector of the tumor suppressor gene semaphorin 3B in lung cancer cells, although IGF‐II partially abrogated its effects 32. A number of recent studies also indicate that IGFBP‐6 may suppress tumor growth via IGF‐independent actions.…”

Section: Discussionmentioning

confidence: 99%

IGF binding protein‐6 expression in vascular endothelial cells is induced by hypoxia and plays a negative role in tumor angiogenesis

Zhang

Lü

et al. 2011

Intl Journal of Cancer

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Hypoxia stimulates tumor angiogenesis by inducing the expression of angiogenic molecules. The negative regulators of this process, however, are not well understood. Here we report that hypoxia induced the expression of insulin-like growth factor binding protein-6 (IGFBP-6), a tumor repressor, in human and rodent vascular endothelial cells (VECs) via a HIF-mediated mechanism. Addition of human IGFBP-6 to cultured human VECs inhibited angiogenesis in vitro. An IGFBP-6 mutant with at least 10,000-fold lower binding affinity for IGFs was an equally potent inhibitor of angiogenesis, suggesting that this action of IGFBP-6 is IGF-independent. The functional relationship between IGFBP-6 and VEGF, a major hypoxia-inducible angiogenic molecule, was examined. While VEGF alone increased angiogenesis in vitro, co-incubation with IGFBP-6 abolished VEGF-stimulated angiogenesis. The in vivo role of IGFBP-6 in angiogenesis was tested in flk1:GFP zebrafish embryos, which exhibit green fluorescence protein in developing vascular endothelium, permitting visualization of developing blood vessels. Injection of human IGFBP-6 mRNA reduced the number of embryonic inter-segmental blood vessels by ∼40%. This anti-angiogenic activity is conserved in zebrafish because expression of zebrafish IGFBP-6b had similar effects. To determine the anti-angiogenic effect of IGFBP-6 in a tumor model, human Rh30 rhabdomyosarcoma cells stably transfected with IGFBP-6 were inoculated into athymic BALB/c nude mice. Vessel density was 52% lower in IGFBP-6-transfected xenografts than in vector control xenografts. These results suggest that the expression of IGFBP-6 in VECs is up-regulated by hypoxia and IGFBP-6 inhibits angiogenesis in vitro and in vivo.

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Identification of IGFBP-6 as an effector of the tumor suppressor activity of SEMA3B

Cited by 22 publications

References 40 publications

N-Terminal Truncated Myb with New Transcriptional Activity Produced Through Use of an Alternative MYB Promoter in Salivary Gland Adenoid Cystic Carcinoma

N-Terminal Truncated Myb with New Transcriptional Activity Produced Through Use of an Alternative MYB Promoter in Salivary Gland Adenoid Cystic Carcinoma

Proteomic analysis of human vitreous humor

IGF binding protein‐6 expression in vascular endothelial cells is induced by hypoxia and plays a negative role in tumor angiogenesis

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