Overexpression of Csk-binding protein contributes to renal cell carcinogenesis

Feng, Xiu; Lu, Xiongbin; Man, Xiao-hua; Zhou, Wei; Jiang, Liping; Knyazev, Pjotr; Lan, Lei; Huang, Qiansheng; Ullrich, Axel; Zhang, Z.; Chen, Zhi

doi:10.1038/onc.2009.185

Cited by 17 publications

(11 citation statements)

References 40 publications

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“…On the other hand, it has been reported that the expression of Cbp is increased in a significant majority of diffuse large B-cell lymphomas (27). In RCC, Cbp is overexpressed in cancer tissues and enhances cell motility and invasiveness, wherein it regulates RhoA activity via its PDZ-binding domain (20). These observations suggest that Cbp has distinct functions depending on the cancer type.…”

Section: Discussionmentioning

confidence: 74%

“…Several recent studies have implicated Cbp in cancer progression. In colon cancer patients, Cbp expression was significantly downregulated in some tumors in comparison with adjacent normal tissues (19), suggesting that Cbp has a tumor suppressor function for some types of cancer; however, other studies have shown that Cbp is overexpressed in renal cell carcinoma (RCC) and serves as a positive regulator of tumor malignancy in RCC patients (20). Thus, it has been suggested that Cbp plays distinct roles in controlling tumor progression depending on the cancer type.…”

Section: Introductionmentioning

confidence: 92%

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The Transmembrane Adaptor Cbp/PAG1 Controls the Malignant Potential of Human Non–Small Cell Lung Cancers That Have c-Src Upregulation

Kanou

Oneyama

Kawahara

et al. 2011

Molecular Cancer Research

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The tyrosine kinase c-Src is upregulated in various human cancers, although the precise regulatory mechanism underlying this upregulation is unclear. We previously reported that a transmembrane adaptor Csk-binding protein (Cbp; PAG1) plays an important role in controlling the cell transformation that is induced by the activation of c-Src. To elucidate the in vivo role of Cbp, we examined the function of Cbp in lung cancer cell lines and tissues. In this study, we found that Cbp was markedly downregulated in human non-small cell lung cancer (NSCLC) cells. The ectopic expression of Cbp suppressed the anchorage-independent growth of the NSCLC cell lines (A549 and Lu99) that had upregulated c-Src, whereas the Cbp expression had little effect on other NSCLC cell lines (PC9 and Lu65) that express normal levels of c-Src. The expression of Cbp suppressed the kinase activity of c-Src in A549 cells by recruiting c-Src and its negative regulator, C-terminal Src kinase (Csk), to lipid rafts. The treatment with Src inhibitors, such as PP2, dasatinib, and saracatinib, also suppressed the growth of A549 cells. Furthermore, Cbp expression attenuated the ability of A549 cells to form tumors in nude mice, invade in vitro, and metastasize in vivo. In addition, we found a significant inverse correlation between the level of Cbp expression and the extent of lymph node metastasis in human lung cancers. These results indicate that Cbp is required for the Csk-mediated inactivation of c-Src and may control the promotion of malignancy in NSCLC tumors that are characterized by c-Src upregulation.

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Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 92%

The Transmembrane Adaptor Cbp/PAG1 Controls the Malignant Potential of Human Non–Small Cell Lung Cancers That Have c-Src Upregulation

Kanou

Oneyama

Kawahara

et al. 2011

Molecular Cancer Research

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“…MELK is thought to bind and activate transcription factors c-JUN and FOXM1 and play a role in maintaining tumor initiating cells [43–46]. Over-expression of CSK-binding protein appeared to contribute to renal cell carcinogenesis in a preclinical study [47]. CHEK2 is activated in response to DNA damage, and is involved in cell cycle arrest, but its role in ccRCC has not been studied [48].…”

Section: Discussionmentioning

confidence: 99%

Kinase Gene Expression Profiling of Metastatic Clear Cell Renal Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets

Ghatalia¹,

Yang²,

Lasseigne³

et al. 2016

PLoS ONE

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Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA) were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79) compared to those that did not develop metastasis for at least 2 years (n = 187). Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001). The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation.

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“…Reversible protein phosphorylation adjusts most process systems of live activities including cell proliferation, development and differentiation, cytoskeleton regulation, apoptosis, neural activity, muscle contraction, metabolism and so on. When the expression or regulation of phosphorylated proteins goes wrong, it can cause changes of functional regulation in organisms which may lead to a series of diseases [4]. More than 50% of oncogenes and oncogene products have the protein tyrosine kinase activity; their abnormal expression leads to regulation disorder of cell proliferation which *Address correspondence to this author at the State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, 33 Life Science Park Road, Changping District, Beijing 102206, P.R.…”

Section: Introductionmentioning

confidence: 99%

Recent Applications of Phosphoproteomics

Chi¹,

Cai²,

Qian

2010

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Protein phosphorylation plays a key role in the regulation of most cellular processes and the disorder of this process often leads to illness or even cancers. Panoramic phosphorylation analysis of organisms known as "phosphoproteomics" has become more important and popular in scientific research fields these days due to its ability of gaining significant information about phosphorylation events and its assistance in understanding how those regulatory functions work in cell. Analytical strategies have been developed for comprehensive analysis of phosphoproteome over the past several years on the aspects of both profiling and quantification. In this review, we will discuss some of the recent applications of phosphoproteomics by using several commonly used technologies, and the applications on study of cell signal transduction pathways and disease-related biomarker and drug targets discovery will also be covered.

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Overexpression of Csk-binding protein contributes to renal cell carcinogenesis

Cited by 17 publications

References 40 publications

The Transmembrane Adaptor Cbp/PAG1 Controls the Malignant Potential of Human Non–Small Cell Lung Cancers That Have c-Src Upregulation

The Transmembrane Adaptor Cbp/PAG1 Controls the Malignant Potential of Human Non–Small Cell Lung Cancers That Have c-Src Upregulation

Kinase Gene Expression Profiling of Metastatic Clear Cell Renal Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets

Recent Applications of Phosphoproteomics

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