Domain-specific function of ShcC docking protein in neuroblastoma cells

Miyake, Izumi; Hakomori, Yuko; Misu, Yoko; Nakadate, Hisaya; Matsuura, Nobuo; Sakamoto, Michiie; Sakai, Ryuichi

doi:10.1038/sj.onc.1208523

Cited by 24 publications

(20 citation statements)

References 36 publications

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“…The anaplastic lymphoma kinase (ALK), involved in the t(2;5) chromosomal rearrangement in anaplastic large cell lymphoma, has been found to be activated due to amplification in neuroblastoma. 34 Although gene amplification of ALK in esophageal carcinomas has not been reported to date, we found a low-level DNA gain at the ALK locus in 44% of the cases. As ALK expression can be detected in several tumor cell lines, Dirks et al 35 conclude that ALK expression may be a physiologic rather than a pathologic phenomenon.…”

Section: Discussionmentioning

confidence: 77%

Genome-wide analysis of genetic alterations in Barrett's adenocarcinoma using single nucleotide polymorphism arrays

Wiech

Nikolopoulos

Weis

et al. 2009

Laboratory Investigation

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We performed genome-wide analysis of copy-number changes and loss of heterozygosity (LOH) in Barrett's esophageal adenocarcinoma by single nucleotide polymorphism (SNP) microarrays to identify associated genomic alterations. DNA from 27 esophageal adenocarcinomas and 14 matching normal tissues was subjected to SNP microarrays. The data were analyzed using dChipSNP software. Copy-number changes occurring in at least 25% of the cases and LOH occurring in at least 19% were regarded as relevant changes. As a validation, fluorescence in situ hybridization (FISH) of 8q24.21 (CMYC) and 8p23.1 (SOX7) was performed. Previously described genomic alterations in esophageal adenocarcinomas could be confirmed by SNP microarrays, such as amplification on 8q (CMYC, confirmed by FISH) and 20q13 or deletion/LOH on 3p (FHIT) and 9p (CDKN2A). Moreover, frequent gains were detected on 2p23.3, 7q11.22, 13q31.1, 14q32.31, 17q23.2 and 20q13.2 harboring several novel candidate genes. The highest copy numbers were seen on 8p23.1, the location of SOX7, which could be demonstrated to be involved in amplification by FISH. A nuclear overexpression of the transcription factor SOX7 could be detected by immunohistochemistry in two amplified tumors. Copy-number losses were seen on 18q21.32 and 20p11.21, harboring interesting candidate genes, such as CDH20 and CST4. Finally, a novel LOH region could be identified on 6p in at least 19% of the cases. In conclusion, SNP microarrays are a valuable tool to detect DNA copynumber changes and LOH at a high resolution. Using this technique, we identified several novel genes and DNA regions associated with esophageal adenocarcinoma. KEYWORDS: Barrett's adenocarcinoma; copy-number changes; esophageal carcinoma; LOH; mapping array; SNP array Genomic alterations, such as amplification, deletion, translocation and loss of heterozygosity (LOH) play an important role in the pathogenesis and progression of cancer due to the activation of oncogenes or inactivation of tumor suppressor genes. Apart from numeric aberrations, such as gene amplification or deletion, which are frequently detected in carcinomas, other genomic changes in carcinogenesis, such as LOH, do not necessarily lead to DNA copy-number gain or loss. Several causes of LOH have been described, including deletion, non-disjunction and reduplication, mitotic recombination and gene conversion. 1 The two-hit model describes a tumor suppressor gene inactivation due to a loss of one allele and mutation of the other allele, resulting in an LOH. 2 Besides detailed investigation of known oncogenes and tumor suppressor genes, screening for novel genomic alterations in different cancers and precursor lesions provides information of molecular mechanisms in carcinogenesis.The incidence of esophageal (Barrett's) adenocarcinoma, mostly arising within the precancerous Barrett's esophagus, with the normal esophageal squamous epithelium changed into intestinal metaplasia, has risen in the past decades in western countries. 3 Screening for chromosomal alterations has bee...

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Section: Discussionmentioning

confidence: 77%

Genome-wide analysis of genetic alterations in Barrett's adenocarcinoma using single nucleotide polymorphism arrays

Wiech

Nikolopoulos

Weis

et al. 2009

Laboratory Investigation

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“…Inhibition of Shc-C function is likely to prevent the function of several RTKs that are important for neuroblastoma cell proliferation, including IGF-1 receptor, ALK, and TrkB, resulting in selective sensitization and enhanced apoptosis of neuroblastoma cells. High levels of phosphorylated Shc-C (but not IRS-2 or PLC-g), have been observed in stable complexes with ALK in neuroblastoma cell lines and tissue samples with ALK amplification, indicating that this RTK acts primarily through the Shc/MAPK proliferative pathway (Miyake et al, 2005;Miyake et al, 2009).…”

Section: Cathepsins Regulate Igf-1 Signaling In Neuroblastomamentioning

confidence: 99%

“…Shc-C (Rai/N-Shc) is a neuronalspecific adapter protein and may be a better target for cancers of the neuronal system (O'Bryan et al, 1996;Pelicci et al, 1996;Nakamura et al, 1998;Tanabe et al, 1998). Shc-C mRNA levels are elevated in most neuroblastoma cell lines, especially those with N-myc or anaplastic lymphoma kinase (ALK) amplification, and are particularly elevated in tumor samples from patients with a poor prognosis (Miyake et al, 2005(Miyake et al, , 2009Terui et al, 2005). We showed that cathepsin inhibitor treatment causes a greater shift of Shc-C into denser organelles than seen for Shc-A, indicating that this neuronal-specific Fractions were immunoblotted as described in Materials and Methods.…”

Section: Cathepsins Regulate Igf-1 Signaling In Neuroblastomamentioning

confidence: 99%

Cathepsin Inhibition Prevents Autophagic Protein Turnover and Downregulates Insulin Growth Factor-1 Receptor-Mediated Signaling in Neuroblastoma

Soori

Mason

2015

Journal of Pharmacology and Experimental Therapeutics

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Inhibition of the major lysosomal proteases, cathepsins B, D, and L, impairs growth of several cell types but leads to apoptosis in neuroblastoma. The goal of this study was to examine the mechanisms by which enzyme inhibition could cause cell death. Cathepsin inhibition caused cellular accumulation of fragments of the insulin growth factor 1 (IGF-1) receptor. The fragments were located in dense organelles that were characterized as autophagosomes. This novel discovery provides the first clear link between lysosomal function, autophagy, and IGF-1-mediated cell proliferation. A more in-depth analysis of the IGF1 signaling pathway revealed that the mitogen-activated protein kinase (MAPK) cell-proliferation pathway was impaired in inhibitor treated cells, whereas the Akt cell survival pathway remained functional. Shc, an adapter protein that transmits IGF-1 signaling through the MAPK pathway, was sequestered in autophagosomes; whereas IRS-2, an adapter protein that transmits IGF-1 signaling through the Akt pathway, was unaffected by cathepsin inhibition. Furthermore, Shc was sequestered in autophagosomes as its active form, indicating that autophagy is a key mechanism for downregulating IGF-1-induced cell proliferation. Cathepsin inhibition had a greater effect on autophagic sequestration of the neuronal specific adapter protein, Shc-C, than ubiquitously expressed Shc-A, providing mechanistic support for the enhanced sensitivity of neuronally derived tumor cells. We also observed impaired activation of MAPK by epidermal growth factor treatment in inhibitor-treated cells. The Shc adapter proteins are central to transducing proliferation signaling by a range of receptor tyrosine kinases; consequently, cathepsin inhibition may become an important therapeutic approach for treating neuroblastoma and other tumors of neuronal origin.

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“…Anti -Flag-M2 antibody was obtained from Sigma. Polyclonal antibodies against p130Cas (Cas2 and Cas3) and phosphospecific polyclonal antibody P-Cas460Y were used as described previously (30,35). Another phosphospecific antibody, P-Cas766Y, was generated by immunizing rabbits with a synthetic phosphopeptide, CMEDpYDpYVHL, which includes the phosphotyrosine-containing motifs in the Src-binding domain of p130Cas, after being conjugated with thymoglobulin.…”

Section: Antibodies and Reagentsmentioning

confidence: 99%

Hyperphosphorylated Cortactin in Cancer Cells Plays an Inhibitory Role in Cell Motility

Jia¹,

Uekita²,

Sakai³

2008

Molecular Cancer Research

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Cortactin is frequently overexpressed in cancer cells, and changes of the levels of its tyrosine phosphorylation have been observed in several cancer cells. However, how the expression level and phosphorylation state of cortactin would influence the ultimate cellular function of cancer cells is unknown. In this study, we analyzed the role of cortactin in gastric and breast cancer cell lines using RNA interference technique and found that knockdown of cortactin inhibited cell migration in a subset of gastric cancer cells with a lower level of its tyrosine phosphorylation, whereas it greatly enhanced cell migration and increased tyrosine phosphorylation of p130Cas in other subsets of cells with hyperphosphorylated cortactin. Consistent results were obtained when hyperphosphorylation of cortactin was induced in MCF7 breast cancer cells by expressing Fyn tyrosine kinase. Additionally, immunostaining analysis showed that knockdown of hyperphosphorylated cortactin resulted in the recruitment of p130Cas to focal adhesions. These results suggest that cortactin hyperphosphorylation suppresses cell migration possibly through the inhibition of membrane localization and tyrosine phosphorylation of p130Cas. (Mol Cancer Res 2008;6(4):654 -62)

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Domain-specific function of ShcC docking protein in neuroblastoma cells

Cited by 24 publications

References 36 publications

Genome-wide analysis of genetic alterations in Barrett's adenocarcinoma using single nucleotide polymorphism arrays

Genome-wide analysis of genetic alterations in Barrett's adenocarcinoma using single nucleotide polymorphism arrays

Cathepsin Inhibition Prevents Autophagic Protein Turnover and Downregulates Insulin Growth Factor-1 Receptor-Mediated Signaling in Neuroblastoma

Hyperphosphorylated Cortactin in Cancer Cells Plays an Inhibitory Role in Cell Motility

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