Spectrin: Structure, function and disease

Zhang, Rui; Zhang, ChenYu; Zhao, Qi; Li, Donghai

doi:10.1007/s11427-013-4575-0

Cited by 84 publications

(78 citation statements)

References 70 publications

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“…Spectrins are cytoskeletal, heterodimeric proteins composed of alpha and beta subunits, with important roles in maintaining the stability of the cell membrane, promoting adhesion and spreading, regulating Golgi and vesicular transport, and controlling cell cycle progression (58–61). Moreover, β III -spectrin can enhance cell survival through maintenance of the Golgi apparatus and regulation of cell surface receptor vesicular transport, including glutamate receptors (60–62).…”

Section: Resultsmentioning

confidence: 99%

Whole Exome Sequencing Reveals the Order of Genetic Changes during Malignant Transformation and Metastasis in a Single Patient with NF1-plexiform Neurofibroma

Hirbe

Dahiya

Miller

et al. 2015

Clinical Cancer Research

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Purpose Malignant peripheral nerve sheath tumors (MPNSTs) occur at increased frequency in individuals with neurofibromatosis type 1 (NF1), where they likely arise from benign plexiform neurofibroma precursors. While previous studies have employed a variety of discovery approaches to discover genes associated with MPNST pathogenesis, it is currently unclear what molecular events are associated with the evolution of MPNST from plexiform neurofibroma. Experimental Design Whole exome sequencing was performed on biopsy materials representing plexiform neurofibroma (n=3), MPNST, and metastasis from a single individual with NF1 over a 14-year period. Additional validation cases were used to assess candidate genes involved in malignant progression, while a murine MPNST model was employed for functional analysis. Results There was an increasing proportion of cells with a somatic NF1 gene mutation as the tumors progressed from benign to malignant, suggesting a clonal process in MPNST development. Copy number variations, including loss of one copy of the TP53 gene, were identified in the primary tumor and the metastatic lesion, but not in benign precursor lesions. A limited number of genes with non-synonymous somatic mutations (βIII-spectrin and ZNF208) were discovered, several of which were validated in additional primary and metastatic MPNST samples. Lastly, increased βIII-spectrin expression was observed in the majority of MPNSTs, and shRNA-mediated knockdown reduced murine MPNST growth in vivo. Conclusion Collectively, the ability to track the molecular evolution of MPNST in a single individual with NF1 offers new insights into the sequence of genetic events important for disease pathogenesis and progression for future mechanistic study.

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Section: Resultsmentioning

confidence: 99%

Whole Exome Sequencing Reveals the Order of Genetic Changes during Malignant Transformation and Metastasis in a Single Patient with NF1-plexiform Neurofibroma

Hirbe

Dahiya

Miller

et al. 2015

Clinical Cancer Research

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“…Sptbn1 was a member of the OFM, and of the two genes, BMD was altered in mice with perturbed Sptbn1 expression. SPTBN1 is a molecular scaffolding protein that links the actin cytoskeleton to the plasma membrane (Zhang et al, 2013b). Through this role, it has been implicated in the regulation of cell shape, adhesion and TGF-β signaling (Zhang et al, 2013b).…”

Section: Discussionmentioning

confidence: 99%

Integrating GWAS and Co-expression Network Data Identifies Bone Mineral Density Genes SPTBN1 and MARK3 and an Osteoblast Functional Module

et al. 2017

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Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. Genome-wide association studies (GWAS) for BMD have identified dozens of associations; yet, the genes responsible for most associations remain elusive. Here, we used a bone co-expression network to predict causal genes at BMD GWAS loci based on the premise that genes underlying a disease are often functionally related and functionally related genes are often co-expressed. By mapping genes implicated by BMD GWAS onto a bone co-expression network, we predicted and inferred the function of causal genes for 30 of 64 GWAS loci. We experimentally confirmed that two of the genes predicted to be causal, SPTBN1 and MARK3, are potentially responsible for the effects of GWAS loci on Chromosomes 2p16.2 and 14q32.32, respectively. This approach provides a roadmap for the dissection of additional BMD GWAS associations. Furthermore, it should be applicable to GWAS data for a wide range of diseases.

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“…SPTBN1 plays an important role in the determination of cell shape, the arrangement of transmembrane proteins and the organization of organelles [35]. A recent report showed that by regulating the Wnt inhibitor kallistatin, loss of SPTBN1 activates Wnt signaling and promotes progression of hepatocellular carcinoma and Wnt signaling [36].…”

Section: Resultsmentioning

confidence: 99%

Validation of a multi-omics strategy for prioritizing personalized candidate driver genes

et al. 2016

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Significant heterogeneity between different tumors prevents the discovery of cancer driver genes, especially in a patient-specific manner. We previously prioritized five personalized candidate mutation-driver genes in a hyper-mutated hepatocellular carcinoma patient using a multi-omics strategy. However, the roles of the prioritized driver genes and patient-specific mutations in hepatocarcinogenesis are unclear. We investigated the impact of the tumor-mutated allele on structure-function relationship of the encoded protein and assessed both loss- and gain-of-function of these genes and mutations on hepatoma cell behaviors in vitro. The prioritized mutation-driver genes act as tumor suppressor genes and inhibit cell proliferation and migration. In addition, the loss-of-function effect of the patient-specific mutations promoted cell proliferation and migration. Of note, the HNF1A S247T mutation significantly reduced the HNF1A transcriptional activity for hepatocyte nuclear factor 4 alpha (HNF4A) but did not disrupt nuclear localization of HNF1A. The results provide evidence for supporting the validity of our proposed multi-omics strategy, which supplies a new avenue for prioritizing mutation-drivers towards personalized cancer therapy.

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Spectrin: Structure, function and disease

Cited by 84 publications

References 70 publications

Whole Exome Sequencing Reveals the Order of Genetic Changes during Malignant Transformation and Metastasis in a Single Patient with NF1-plexiform Neurofibroma

Whole Exome Sequencing Reveals the Order of Genetic Changes during Malignant Transformation and Metastasis in a Single Patient with NF1-plexiform Neurofibroma

Integrating GWAS and Co-expression Network Data Identifies Bone Mineral Density Genes SPTBN1 and MARK3 and an Osteoblast Functional Module

Validation of a multi-omics strategy for prioritizing personalized candidate driver genes

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