ECT2

Gene Summary

Gene:ECT2; epithelial cell transforming 2
Aliases: ARHGEF31
Location:3q26.1-q26.2
Summary:The protein encoded by this gene is a guanine nucleotide exchange factor and transforming protein that is related to Rho-specific exchange factors and yeast cell cycle regulators. The expression of this gene is elevated with the onset of DNA synthesis and remains elevated during G2 and M phases. In situ hybridization analysis showed that expression is at a high level in cells undergoing mitosis in regenerating liver. Thus, this protein is expressed in a cell cycle-dependent manner during liver regeneration, and is thought to have an important role in the regulation of cytokinesis. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protein ECT2
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
Show (43)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Isoenzymes
  • Survival Rate
  • Adenocarcinoma
  • rac1 GTP-Binding Protein
  • Staging
  • RHOA
  • Lung Cancer
  • Gene Expression Profiling
  • Gene Amplification
  • Cancer Gene Expression Regulation
  • siRNA
  • Disease Progression
  • Gene Expression
  • Up-Regulation
  • Lymphatic Metastasis
  • RTPCR
  • RNA Interference
  • ECT2
  • Transcriptome
  • Squamous Cell Carcinoma
  • Gene Dosage
  • Tumor Suppressor Proteins
  • Signal Transduction
  • Chromosome 3
  • Chromosome Mapping
  • Non-Small Cell Lung Cancer
  • Messenger RNA
  • Neoplastic Cell Transformation
  • Transcription Factors
  • Cell Proliferation
  • DNA Copy Number Variations
  • Proto-Oncogene Proteins
  • Proteomics
  • Guanine Nucleotide Exchange Factors
  • Neoplasm Invasiveness
  • Brain Stem Glioma, Childhood
  • Protein Kinase C
  • Chromosome Aberrations
  • Transfection
  • RHOB
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ECT2 (cancer-related)

Qian J, Hassanein M, Hoeksema MD, et al.
The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers.
Proc Natl Acad Sci U S A. 2015; 112(11):3469-74 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies.

Cheng YS, Lin C, Cheng YP, et al.
Epithelial cell transformation sequence 2 is a potential biomarker of unfavorable survival in human gliomas.
Neurol India. 2014 Jul-Aug; 62(4):406-9 [PubMed] Related Publications
BACKGROUND: High-grade primary gliomas are invasive and have poor outcome. The identification of biomarkers predictive of outcome in patients with gliomas is crucial for clinical follow-up. Epithelial cell transformation sequence 2 (ECT2) modulates cancer invasion, progression, metastasis and cell cycle regulation. However, its role in determining the clinical outcome of human gliomas warrants further elucidation.
MATERIALS AND METHODS: This study hypothesized that ECT2 is over-expressed in human gliomas. We analysis de-linked data (GDS1815/219787_s_at/ECT2) in primary high-grade glioma, and exclude 23 sheets of data without detailed information. An additional database (GDS1962/234992_x_at/ECT2) was also included to evaluation ECT2 gene expression in each pathologic grading.
RESULTS: Analysis of the Gene Expression Omnibus (GEO) profile showed that ECT2 mRNA expression level was higher in WHO grade IV (n = 81) than in grade II (n = 7, P = 0.0126) gliomas and non-tumor controls (n = 23; P = 1.65 Χ 10⁻⁸). Kaplan-Meier analysis showed unfavorable survival in patients with high ECT2 mRNA levels (n = 10) than in those with low ECT2 expression (n = 67) (median survival, 106 vs. 46 weeks, P < 0.0001, by log-rank test, Hazard ratio: 0.07850, 95% CI: 0.02402-0.2565).
CONCLUSIONS: ECT2 expression is positively correlated with WHO pathologic grading and unfavorable survival, suggesting that ECT2 may be a potential therapeutic candidate in human gliomas.

Zhang H, Yin Z, Ning K, et al.
Prognostic value of microRNA-223/epithelial cell transforming sequence 2 signaling in patients with osteosarcoma.
Hum Pathol. 2014; 45(7):1430-6 [PubMed] Related Publications
MicroRNA-223 (miR-223) has been demonstrated to be implicated in cell proliferation and cell cycle progression of osteosarcoma cell lines by regulating its target gene epithelial cell transforming sequence 2 (ECT2). However, the clinical significance of the deregulation of the miR-223/Ect2 axis in human osteosarcoma has not been fully elucidated. To address this problem, we firstly showed that the expression levels of miR-223 and Ect2 messenger RNA were, respectively, down-regulated and up-regulated in osteosarcoma tissues compared with those in noncancerous bone tissues significantly (both P < .001), according to the results of quantitative real-time reverse transcription-polymerase chain reaction. Notably, miR-223 down-regulation was negatively correlated with Ect2 messenger RNA up-regulation in osteosarcoma tissues (r = -0.68, P = .01). Then, the combined low miR-223 expression and high Ect2 expression (miR-223-low/Ect2-high) was significantly associated with high tumor grade (P = .01), poor response to chemotherapy (P = .01), positive metastasis (P < .001), and recurrence (P < .001) of osteosarcomas. Moreover, patients with miR-223-low/Ect2-high expression had the shortest overall survival (P < .001) and disease-free survival (P < .001) compared with patients in the other 3 groups (miR-223-low/Ect2-low, miR-223-high/Ect2-high, and miR-223-high/Ect2-low). Furthermore, the multivariate analysis identified miR-223/Ect2 expression and the status of metastasis as independent prognostic factors for overall survival and disease-free survival. In conclusion, our data offer convincing evidence that the deregulation of miR-223 and its target gene ECT2 may be associated with the aggressive tumor progression of human osteosarcoma. Of note, the combined miR-223 down-regulation and Ect2 up-regulation may be a possible marker of poor prognosis in this malignancy.

Murata Y, Minami Y, Iwakawa R, et al.
ECT2 amplification and overexpression as a new prognostic biomarker for early-stage lung adenocarcinoma.
Cancer Sci. 2014; 105(4):490-7 [PubMed] Related Publications
Genetic abnormality in early-stage lung adenocarcinoma was examined to search for new prognostic biomarkers. Six in situ lung adenocarcinomas and nine small but invasive adenocarcinomas were examined by array-comparative genomic hybridization, and candidate genes of interest were screened. To examine gene abnormalities, 83 cases of various types of lung carcinoma were examined by quantitative real-time genomic PCR and immunohistochemistry. The results were then verified using another set of early-stage adenocarcinomas. Array-comparative genomic hybridization indicated frequent amplification at chromosome 3q26. Of the seven genes located in this region, we focused on the epithelial cell transforming sequence 2 (ECT2) oncogene, as ECT2 amplification was detected only in invasive adenocarcinoma, and not in in situ carcinoma. Quantitative PCR and immunohistochemistry analyses also detected overexpression of ECT2 in invasive adenocarcinoma, and this was correlated with both the Ki-67 labeling index and mitotic index. In addition, it was associated with disease-free survival and overall survival of patients with lung adenocarcinoma. These results were verified using another set of early-stage adenocarcinomas resected at another hospital. Abnormality of the ECT2 gene occurs at a relatively early stage of lung adenocarcinogenesis and would be applicable as a new biomarker for prognostication of patients with lung adenocarcinoma.

Wang Y, Hill KS, Fields AP
PKCι maintains a tumor-initiating cell phenotype that is required for ovarian tumorigenesis.
Mol Cancer Res. 2013; 11(12):1624-35 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
UNLABELLED: Protein kinase Cι (PKCι) has oncogenic potential and is an attractive therapeutic target for treatment of lung cancer, particularly those tumors that express elevated PKCι. However, whether PKCι is a viable target in ovarian cancer is unknown, and virtually nothing is known about the mechanism by which PKCι drives ovarian tumorigenesis. Here, it is demonstrated that PKCι maintains a tumor-initiating cell (TIC) phenotype that drives ovarian tumorigenesis. A highly tumorigenic population of cells from human ovarian cancer cell lines exhibit cancer stem-like TIC properties, including self-renewal, clonal expansion, expression of stem-related genes, enhanced transformed growth in vitro, and aggressive tumor-initiating activity in vivo. Genetic disruption of PKCι inhibits the proliferation, clonal expansion, anchorage-independent growth, and enhanced tumorigenic properties of ovarian TICs. Biochemical analysis demonstrates that PKCι acts through its oncogenic partner Ect2 to activate a MEK/ERK signaling axis that drives the ovarian TIC phenotype. Genomic analysis reveals that PKCι and Ect2 are coordinately amplified and overexpressed in the majority of primary ovarian serous tumors, and these tumors exhibit evidence of an active PKCι-Ect2 signaling axis in vivo. Finally, this study reveals that auranofin, a potent and selective inhibitor of oncogenic PKCι signaling, inhibits the tumorigenic properties of ovarian TIC cells in vitro and in vivo. These data demonstrate that PKCι is required for a TIC phenotype in ovarian cancer, and that auranofin is an attractive therapeutic option to target deadly ovarian TICs in ovarian cancer patients.
IMPLICATIONS: PKCι drives a tumor-initiating cell phenotype in ovarian cancer cells that can be therapeutically targeted with auranofin, a small molecule inhibitor of PKCι signaling.

Cook DR, Rossman KL, Der CJ
Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease.
Oncogene. 2014; 33(31):4021-35 [PubMed] Related Publications
The aberrant activity of Ras homologous (Rho) family small GTPases (20 human members) has been implicated in cancer and other human diseases. However, in contrast to the direct mutational activation of Ras found in cancer and developmental disorders, Rho GTPases are activated most commonly in disease by indirect mechanisms. One prevalent mechanism involves aberrant Rho activation via the deregulated expression and/or activity of Rho family guanine nucleotide exchange factors (RhoGEFs). RhoGEFs promote formation of the active GTP-bound state of Rho GTPases. The largest family of RhoGEFs is comprised of the Dbl family RhoGEFs with 70 human members. The multitude of RhoGEFs that activate a single Rho GTPase reflects the very specific role of each RhoGEF in controlling distinct signaling mechanisms involved in Rho activation. In this review, we summarize the role of Dbl RhoGEFs in development and disease, with a focus on Ect2 (epithelial cell transforming squence 2), Tiam1 (T-cell lymphoma invasion and metastasis 1), Vav and P-Rex1/2 (PtdIns(3,4,5)P3 (phosphatidylinositol (3,4,5)-triphosphate)-dependent Rac exchanger).

Samuel N, Sayad A, Wilson G, et al.
Integrated genomic, transcriptomic, and RNA-interference analysis of genes in somatic copy number gains in pancreatic ductal adenocarcinoma.
Pancreas. 2013; 42(6):1016-26 [PubMed] Related Publications
OBJECTIVES: This study used an integrated analysis of copy number, gene expression, and RNA interference screens for identification of putative driver genes harbored in somatic copy number gains in pancreatic ductal adenocarcinoma (PDAC).
METHODS: Somatic copy number gain data on 60 PDAC genomes were extracted from public data sets to identify genomic loci that are recurrently gained. Array-based data from a panel of 29 human PDAC cell lines were used to quantify associations between copy number and gene expression for the set of genes found in somatic copy number gains. The most highly correlated genes were assessed in a compendium of pooled short hairpin RNA screens on 27 of the same human PDAC cell lines.
RESULTS: A catalog of 710 protein-coding and 46 RNA genes mapping to 20 recurrently gained genomic loci were identified. The gene set was further refined through stringent integration of copy number, gene expression, and RNA interference screening data to uncover 34 candidate driver genes.
CONCLUSIONS: Among the candidate genes from the integrative analysis, ECT2 was found to have significantly higher essentiality in specific PDAC cell lines with genomic gains at the 3q26.3 locus, which harbors this gene, suggesting that ECT2 may play an oncogenic role in the PDAC neoplastic process.

Matthews HK, Baum B
The metastatic cancer cell cortex: an adaptation to enhance robust cell division in novel environments?
Bioessays. 2012; 34(12):1017-20 [PubMed] Related Publications
To metastasize, cancer cells must be able to complete cell division in environments very different from their tissue of origin. We suggest that mitotic cell rounding, aided by several actin-regulatory oncogenes, may facilitate this process in a robust, context-independent manner.

Wondergem B, Zhang Z, Huang D, et al.
Expression of the PTTG1 oncogene is associated with aggressive clear cell renal cell carcinoma.
Cancer Res. 2012; 72(17):4361-71 [PubMed] Related Publications
The pituitary tumor transforming gene (PTTG1) is a recently discovered oncogene implicated in malignant progression of both endocrine and nonendocrine malignancies. Clear cell renal cell carcinoma (ccRCC) is cytogenetically characterized by chromosome 3p deletions that harbor the ccRCC-related von Hippel-Lindau, PBRM1, BAP1, and SETD2 tumor suppressor genes, along with chromosome 5q amplifications where the significance has been unclear. PTTG1 localizes to the chromosome 5q region where amplifications occur in ccRCC. In this study, we report a functional role for PTTG1 in ccRCC tumorigenesis. PTTG1 was amplified in ccRCC, overexpressed in tumor tissue, and associated with high-grade tumor cells and poor patient prognosis. In preclinical models, PTTG1 ablation reduced tumorigenesis and invasion. An analysis of gene expression affected by PTTG1 indicated an association with invasive and metastatic disease. PTTG1-dependent expression of the RhoGEF proto-oncogene ECT2 was observed in a number of ccRCC cell lines. Moreover, ECT2 expression correlated with PTTG1 expression and poor clinical features. Together, our findings reveal features of PTTG1 that are consistent with its identification of an oncogene amplified on chromsome 5q in ccRCC, where it may offer a novel therapeutic target of pathologic significance in this disease.

Jiang Z, Gui S, Zhang Y
Analysis of differential gene expression in plurihormonal pituitary adenomas using bead-based fiber-optic arrays.
J Neurooncol. 2012; 108(3):341-8 [PubMed] Related Publications
Plurihormonal pituitary adenomas (PHPAs) are defined as those pituitary adenomas secreting two or more hormones that differ in chemical composition, immunoreactivity, and biologic effects. Since the pathogenesis of these adenomas is not well understood, our study aimed to explore mechanisms underlying the pathogenesis of PHPAs. We used bead-based fiber-optic arrays (Illumina Human GeneChip WG-6 v3.0) to examine the gene expression profiles in seven PHPAs compared with three normal pituitary glands. Four differentially expressed genes were chosen randomly for validation by quantitative real-time reverse-transcription polymerase chain reaction. We then performed pathway analysis of all differentially expressed genes using the Kyoto Encyclopedia of Genes and Genomes. Our array analysis showed significant increases in the expression of 6 genes and decreases in 334 genes and 15 expressed sequence tags in the PHPAs. Bioinformatic analysis showed that genes HIGD1B, EPS8, ECT2, and BTG2 might play an important role in the tumorigenesis and progression of PHPAs. Pathway analysis showed that the p53 and Notch signaling pathways may play an important role in tumorigenesis and progression of PHPAs, and extracellular matrix (ECM)-receptor interactions likely play a role in the inhibition of invasion and metastasis in these tumors. Our data suggested that there are numerous aberrantly expressed genes and pathways involved in the pathogenesis of PHPAs. Bead-based fiber-optic arrays combined with pathway analysis of gene expression data appears to be a valid method for investigating the pathogenesis of tumors.

Fortin SP, Ennis MJ, Schumacher CA, et al.
Cdc42 and the guanine nucleotide exchange factors Ect2 and trio mediate Fn14-induced migration and invasion of glioblastoma cells.
Mol Cancer Res. 2012; 10(7):958-68 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
Malignant glioblastomas are characterized by their ability to infiltrate into normal brain. We previously reported that binding of the multifunctional cytokine TNF-like weak inducer of apoptosis (TWEAK) to its receptor fibroblast growth factor-inducible 14 (Fn14) induces glioblastoma cell invasion via Rac1 activation. Here, we show that Cdc42 plays an essential role in Fn14-mediated activation of Rac1. TWEAK-treated glioma cells display an increased activation of Cdc42, and depletion of Cdc42 using siRNA abolishes TWEAK-induced Rac1 activation and abrogates glioma cell migration and invasion. In contrast, Rac1 depletion does not affect Cdc42 activation by Fn14, showing that Cdc42 mediates TWEAK-stimulated Rac1 activation. Furthermore, we identified two guanine nucleotide exchange factors (GEF), Ect2 and Trio, involved in TWEAK-induced activation of Cdc42 and Rac1, respectively. Depletion of Ect2 abrogates both TWEAK-induced Cdc42 and Rac1 activation, as well as subsequent TWEAK-Fn14-directed glioma cell migration and invasion. In contrast, Trio depletion inhibits TWEAK-induced Rac1 activation but not TWEAK-induced Cdc42 activation. Finally, inappropriate expression of Fn14 or Ect2 in mouse astrocytes in vivo using an RCAS vector system for glial-specific gene transfer in G-tva transgenic mice induces astrocyte migration within the brain, corroborating the in vitro importance of the TWEAK-Fn14 signaling cascade in glioblastoma invasion. Our results suggest that the TWEAK-Fn14 signaling axis stimulates glioma cell migration and invasion through two GEF-GTPase signaling units, Ect2-Cdc42 and Trio-Rac1. Components of the Fn14-Rho GEF-Rho GTPase signaling pathway present innovative drug targets for glioma therapy.

Vazquez-Mena O, Medina-Martinez I, Juárez-Torres E, et al.
Amplified genes may be overexpressed, unchanged, or downregulated in cervical cancer cell lines.
PLoS One. 2012; 7(3):e32667 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
Several copy number-altered regions (CNAs) have been identified in the genome of cervical cancer, notably, amplifications of 3q and 5p. However, the contribution of copy-number alterations to cervical carcinogenesis is unresolved because genome-wide there exists a lack of correlation between copy-number alterations and gene expression. In this study, we investigated whether CNAs in the cell lines CaLo, CaSki, HeLa, and SiHa were associated with changes in gene expression. On average, 19.2% of the cell-line genomes had CNAs. However, only 2.4% comprised minimal recurrent regions (MRRs) common to all the cell lines. Whereas 3q had limited common gains (13%), 5p was entirely duplicated recurrently. Genome-wide, only 15.6% of genes located in CNAs changed gene expression; in contrast, the rate in MRRs was up to 3 times this. Chr 5p was confirmed entirely amplified by FISH; however, maximum 33.5% of the explored genes in 5p were deregulated. In 3q, this rate was 13.4%. Even in 3q26, which had 5 MRRs and 38.7% recurrently gained SNPs, the rate was only 15.1%. Interestingly, up to 19% of deregulated genes in 5p and 73% in 3q26 were downregulated, suggesting additional factors were involved in gene repression. The deregulated genes in 3q and 5p occurred in clusters, suggesting local chromatin factors may also influence gene expression. In regions amplified discontinuously, downregulated genes increased steadily as the number of amplified SNPs increased (p<0.01, Spearman's correlation). Therefore, partial gene amplification may function in silencing gene expression. Additional genes in 1q, 3q and 5p could be involved in cervical carcinogenesis, specifically in apoptosis. These include PARP1 in 1q, TNFSF10 and ECT2 in 3q and CLPTM1L, AHRR, PDCD6, and DAP in 5p. Overall, gene expression and copy-number profiles reveal factors other than gene dosage, like epigenetic or chromatin domains, may influence gene expression within the entirely amplified genome segments.

Wang SM, Ooi LL, Hui KM
Upregulation of Rac GTPase-activating protein 1 is significantly associated with the early recurrence of human hepatocellular carcinoma.
Clin Cancer Res. 2011; 17(18):6040-51 [PubMed] Related Publications
PURPOSE: To assess the significance of Rac GTPase-activating protein 1 (RACGAP1) expression in identifying HBV-positive human hepatocellular carcinoma (HCC) patients who are at high risk for recurrent disease.
EXPERIMENTAL DESIGN: The prognostic significance of RACGAP1 was compared with clinicopathologic parameters available at diagnosis using multivariate and log-rank test. RACGAP1 expression and outcome in recurrence was compared between 35 patients with recurrence and 41 patients without recurrence using Kaplan-Meier analysis. RACGAP1-targeted molecules and pathways were identified and characterized by inhibition with siRNA duplexes.
RESULTS: Kaplan-Meier analysis showed that the level of RACGAP1 expression is sufficient to predict the early recurrence of HCC: high RACGAP1 expression correlates with high risk of postresection recurrent HCC (P < 0.0005). Silencing of RACGAP1 in Hep3B and MHCC97-H HCC cells with high endogenous RACGAP1 expression inhibited cell migration and invasion. Using Ingenuity Pathway Analysis, the target molecules silenced in the RACGAP1 interactome were mostly genes related to the mitotic roles of the polo-like kinases. These included PRC1, AURKB, CDC2, ECT2, KIF23, PAK1, and PPP2R5E. In providing clinical corroboration of these results, when expression of these transcripts was analyzed in an expression database that we have established previously for HBV-positive HCC patients, these genes was mostly upregulated in patients who exhibited early recurrent disease and hence provided important corroboration of these results.
CONCLUSIONS: siRNA-silencing RACGAP1 mainly targeted genes in an interactome clinically relevant to early HCC recurrence. Besides being an independent informative prognostic biomarker, RACGAP1 could also be a potential molecular target for designing therapeutic strategies for HCC.

Hirooka S, Akashi T, Ando N, et al.
Localization of the invadopodia-related proteins actinin-1 and cortactin to matrix-contact-side cytoplasm of cancer cells in surgically resected lung adenocarcinomas.
Pathobiology. 2011; 78(1):10-23 [PubMed] Related Publications
OBJECTIVES: Actin-associated proteins at cell-matrix-contact sites form invadopodia in cancer cells and participate in migration, matrix degradation and invasion. We investigated an alteration of subcellular localization of invadopodia-related actin-associated proteins, actinin-1 and cortactin, in lung adenocarcinomas, its clinical significance, and its possible regulatory factors.
METHODS: Invadopodia-related proteins, actinin-1 and cortactin, were immunohistochemically examined in 90 cases of lung adenocarcinomas. Expression of invadopodia-associated proteins and their possible regulators in lung adenocarcinomas were examined by real-time RT-PCR, database search, and immunohistochemistry.
RESULTS: Actinin-1 and cortactin showed matrix-contact-side localization in adenocarcinoma cells, but rarely in normal bronchiolar epithelial cells, alveolar cells, or precursor lesion atypical adenomatous hyperplasia cells. Immunoelectron-microscopic examination of adenocarcinoma cells revealed actinin-1 localization to matrix-contact-side cytoplasm with cytoplasmic protrusions. Matrix-contact-side localization of actinin-1 and cortactin was correlated with tumor stages, lymph node metastasis, vascular permeation, and loss of basement membrane. The tumor-specific survival rate was worse for the group in which matrix-contact-side localization of cortactin was high than for the low group. mRNA of the Rho guanine exchange factor epithelial cell transforming sequence-2 (Ect2) tended to be overexpressed in lung adenocarcinomas and cytoplasmic expression of Ect2 tended to be correlated with matrix-contact-side localization of actinin-1.
CONCLUSION: Matrix-contact-side localization of invadopodia-related proteins in the lung adenocarcinoma cells were correlated with invasion, metastasis, and poor prognosis. Ect2 was a possible regulator of matrix-contact-side localization of invadopodia-related proteins.

Srougi MC, Burridge K
The nuclear guanine nucleotide exchange factors Ect2 and Net1 regulate RhoB-mediated cell death after DNA damage.
PLoS One. 2011; 6(2):e17108 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
Commonly used antitumor treatments, including radiation and chemotherapy, function by damaging the DNA of rapidly proliferating cells. However, resistance to these agents is a predominant clinical problem. A member of the Rho family of small GTPases, RhoB has been shown to be integral in mediating cell death after ionizing radiation (IR) or other DNA damaging agents in Ras-transformed cell lines. In addition, RhoB protein expression increases after genotoxic stress, and loss of RhoB expression causes radio- and chemotherapeutic resistance. However, the signaling pathways that govern RhoB-induced cell death after DNA damage remain enigmatic. Here, we show that RhoB activity increases in human breast and cervical cancer cell lines after treatment with DNA damaging agents. Furthermore, RhoB activity is necessary for DNA damage-induced cell death, as the stable loss of RhoB protein expression using shRNA partially protects cells and prevents the phosphorylation of c-Jun N-terminal kinases (JNKs) and the induction of the pro-apoptotic protein Bim after IR. The increase in RhoB activity after genotoxic stress is associated with increased activity of the nuclear guanine nucleotide exchange factors (GEFs), Ect2 and Net1, but not the cytoplasmic GEFs p115 RhoGEF or Vav2. Importantly, loss of Ect2 and Net1 via siRNA-mediated protein knock-down inhibited IR-induced increases in RhoB activity, reduced apoptotic signaling events, and protected cells from IR-induced cell death. Collectively, these data suggest a mechanism involving the nuclear GEFs Ect2 and Net1 for activating RhoB after genotoxic stress, thereby facilitating cell death after treatment with DNA damaging agents.

Jung Y, Lee S, Choi HS, et al.
Clinical validation of colorectal cancer biomarkers identified from bioinformatics analysis of public expression data.
Clin Cancer Res. 2011; 17(4):700-9 [PubMed] Related Publications
PURPOSE: Identification of novel biomarkers of cancer is important for improved diagnosis, prognosis, and therapeutic intervention. This study aimed to identify marker genes of colorectal cancer (CRC) by combining bioinformatics analysis of gene expression data and validation experiments using patient samples and to examine the potential connection between validated markers and the established oncogenes such as c-Myc and K-ras.
EXPERIMENTAL DESIGN: Publicly available data from GenBank and Oncomine were meta-analyzed leading to 34 candidate marker genes of CRC. Multiple case-matched normal and tumor tissues were examined by RT-PCR for differential expression, and 9 genes were validated as CRC biomarkers. Statistical analyses for correlation with major clinical parameters were carried out, and RNA interference was used to examine connection with major oncogenes.
RESULTS: We show with high confidence that 9 (ECT2, ETV4, DDX21, RAN, S100A11, RPS4X, HSPD1, CKS2, and C9orf140) of the 34 candidate genes are expressed at significantly elevated levels in CRC tissues compared to normal tissues. Furthermore, high-level expression of RPS4X was associated with nonmucinous cancer cell type and that of ECT2 with lack of lymphatic invasion while upregulation of CKS2 was correlated with early tumor stage and lack of family history of CRC. We also demonstrate that RPS4X and DDX21 are regulatory targets of c-Myc and ETV4 is downstream to K-ras signaling.
CONCLUSIONS: We have identified multiple novel biomarkers of CRC. Further analyses of their function and connection to signaling pathways may reveal potential value of these biomarkers in diagnosis, prognosis, and treatment of CRC.

Justilien V, Jameison L, Der CJ, et al.
Oncogenic activity of Ect2 is regulated through protein kinase C iota-mediated phosphorylation.
J Biol Chem. 2011; 286(10):8149-57 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
The Rho GTPase guanine nucleotide exchange factor Ect2 is genetically and biochemically linked to the PKCι oncogene in non-small cell lung cancer (NSCLC). Ect2 is overexpressed and mislocalized to the cytoplasm of NSCLC cells where it binds the oncogenic PKCι-Par6 complex, leading to activation of the Rac1 small GTPase. Here, we identify a previously uncharacterized phosphorylation site on Ect2, threonine 328, that serves to regulate the oncogenic activity of Ect2 in NSCLC cells. PKCι directly phosphorylates Ect2 at Thr-328 in vitro, and RNAi-mediated knockdown of either PKCι or Par6 leads to a decrease in phospho-Thr-328 Ect2, indicating that PKCι regulates Thr-328 Ect2 phosphorylation in NSCLC cells. Both wild-type Ect2 and a phosphomimetic T328D Ect2 mutant bind the PKCι-Par6 complex, activate Rac1, and restore transformed growth and invasion when expressed in NSCLC cells made deficient in endogenous Ect2 by RNAi-mediated knockdown. In contrast, a phosphorylation-deficient T328A Ect2 mutant fails to bind the PKCι-Par6 complex, activate Rac1, or restore transformation. Our data support a model in which PKCι-mediated phosphorylation regulates Ect2 binding to the oncogenic PKCι-Par6 complex thereby activating Rac1 activity and driving transformed growth and invasion.

Iyoda M, Kasamatsu A, Ishigami T, et al.
Epithelial cell transforming sequence 2 in human oral cancer.
PLoS One. 2010; 5(11):e14082 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
BACKGROUND: Epithelial cell transforming sequence 2 (ECT2) is a guanine nucleotide exchange factor for Rho family GTPase, which has been implicated in the malignant phenotype of human cancers. Little is known about the effect of a high level of ECT2 in regulating oral cancer cell behavior. In this study, we investigated the involvement of ECT2 in oral squamous cell carcinoma (OSCC).
METHODOLOGY/PRINCIPAL FINDINGS: We analyzed ECT2 expression in OSCC-derived cell lines and primary OSCCs compared with matched normal tissue (n = 96) by quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry. We then evaluated the correlation between the ECT2 expression status in primary OSCCs and the clinicopathological features. ECT2 expression was significantly up-regulated in OSCCs in vitro and in vivo (p<0.05). Among the clinical variables analyzed, higher ECT2 expression also was associated with the TNM stage grading (p<0.05). When we performed functional analyses of ECT2 in OSCC-derived cells using the shRNA system, the cellular proliferation of the ECT2 knockdown cells decreased significantly compared with the control cells (p<0.05). Cell cycle analysis by flow cytometry showed arrest of cell cycle progression at the G1 phase in the ECT2 knockdown cells. We also found up-regulation of the Cip/Kip family of the cyclin-dependent kinase inhibitors, p21(cip1) and p27(kip1), and down-regulation of cyclin D1, cyclin E, and CDK4. These data suggested that the elevated Cip/Kip family induced inhibition of the cyclin D1-CDK complex activity leading to cell cycle arrest at the G1 phase.
CONCLUSIONS/SIGNIFICANCE: Our results proposed for the first time that ECT2 is an indicator of cellular proliferation in OSCCs and that ECT2 might be a potential therapeutic target for the development of new treatments for OSCCs.

Justilien V, Fields AP
Ect2 links the PKCiota-Par6alpha complex to Rac1 activation and cellular transformation.
Oncogene. 2009; 28(41):3597-607 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
Protein kinase Ciota (PKCiota) promotes non-small cell lung cancer (NSCLC) by binding to Par6alpha and activating a Rac1-Pak-Mek1,2-Erk1,2 signaling cascade. The mechanism by which the PKCiota-Par6alpha complex regulates Rac1 is unknown. Here we show that epithelial cell transforming sequence 2 (Ect2), a guanine nucleotide exchange factor for Rho family GTPases, is coordinately amplified and overexpressed with PKCiota in NSCLC tumors. RNA interference-mediated knockdown of Ect2 inhibits Rac1 activity and blocks transformed growth, invasion and tumorigenicity of NSCLC cells. Expression of constitutively active Rac1 (RacV12) restores transformation to Ect2-deficient cells. Interestingly, the role of Ect2 in transformation is distinct from its well-established role in cytokinesis. In NSCLC cells, Ect2 is mislocalized to the cytoplasm where it binds the PKCiota-Par6alpha complex. RNA interference-mediated knockdown of either PKCiota or Par6alpha causes Ect2 to redistribute to the nucleus, indicating that the PKCiota-Par6alpha complex regulates the cytoplasmic localization of Ect2. Our data indicate that Ect2 and PKCiota are genetically and functionally linked in NSCLC, acting to coordinately drive tumor cell proliferation and invasion through formation of an oncogenic PKCiota-Par6alpha-Ect2 complex.

Boelens MC, Kok K, van der Vlies P, et al.
Genomic aberrations in squamous cell lung carcinoma related to lymph node or distant metastasis.
Lung Cancer. 2009; 66(3):372-8 [PubMed] Related Publications
About 50% of patients presenting with resectable lung cancer develop distant metastases within 5 years. Genomic markers predicting metastatic behaviour of squamous cell lung carcinoma (SCC) are currently underexposed. We analyzed a cohort of patients with primary SCC using array-based comparative genomic hybridization (aCGH) to identify which genomic aberrations are related to metastatic behaviour. The cohort consisted of 34 patients with a follow-up of at least 5 years, 8 with metastases in regional lymph nodes only and 26 patients without any metastases at the time of surgery. Eleven of the latter 26 developed metastases in distant organs within 3 years after surgery. Copy number changes observed in at least 40% of all SCC included gains at chromosomal arms 3q, 5p, 8q, 19q, 20p, 22q and losses at 3p, 4p, 4q, 5q, 8p and 9p. High copy number amplifications were observed at 2p15-p16, 3q24-q29, 8p11-p12, 8q23-q24, and 12p12, containing candidate oncogenes such as BCL11A, REL, ECT2, PIK3CA, ADAM9, MYC and KRAS. Amplification of 2p15-p16 is a novel finding in SCC. Another novel finding is the homozygous deletion observed at 4q33-34.1 in 15% of the SCC cases. Gains at 7q36, 8p12, 10q22, 12p12, loss at 4p14 and the homozygous deletions at 4q occurred significantly more frequent in SCC from patients with lymph node metastases only. SCC from patients with distant metastases showed a significantly higher gain frequency at 8q22-q24 and loss at 8p23 and 13q21, and a significantly lower gain frequency at 2p12 and 2p16 and loss at 11q25 compared with SCC from patients without metastases. Of these, gains at 7q, 8p and 10q were restricted to SCC with lymph node metastasis and gain at 8q was restricted to patients with distant metastasis. Two genomic aberrations, i.e. loss of 4p and gain of 19q12 were observed more frequently in SCC with only lymph node metastases as compared to SCC with distant metastases. In conclusion, we identified genomic aberrations in primary SCC that were related to lymph node or distant metastases.

Hirata D, Yamabuki T, Miki D, et al.
Involvement of epithelial cell transforming sequence-2 oncoantigen in lung and esophageal cancer progression.
Clin Cancer Res. 2009; 15(1):256-66 [PubMed] Related Publications
PURPOSE: This study aims to isolate potential molecular targets for diagnosis, treatment, and/or prevention of lung and esophageal carcinomas.
EXPERIMENTAL DESIGN: We screened for genes that were frequently overexpressed in the tumors through gene expression profile analyses of 101 lung cancers and 19 esophageal squamous cell carcinomas (ESCC) by cDNA microarray consisting of 27,648 genes or expressed sequence tags. In this process, we identified epithelial cell transforming sequence 2 (ECT2) as a candidate. Tumor tissue microarray was applied to examine the expression of ECT2 protein in 242 archived non-small-cell lung cancers (NSCLC) and 240 ESCC specimens and to investigate its prognostic value. A role of ECT2 in lung and esophageal cancer cell growth and/or survival was examined by small interfering RNA experiments. Cellular invasive activity of ECT2 in mammalian cells was examined using Matrigel assays.
RESULTS: Northern blot and immunohistochemical analyses detected expression of ECT2 only in testis among 23 normal tissues. Immunohistochemical staining showed that a high level of ECT2 expression was associated with poor prognosis for patients with NSCLC (P = 0.0004) as well as ESCC (P = 0.0088). Multivariate analysis indicated it to be an independent prognostic factor for NSCLC (P = 0.0005). Knockdown of ECT2 expression by small interfering RNAs effectively suppressed lung and esophageal cancer cell growth. In addition, induction of exogenous expression of ECT2 in mammalian cells promoted cellular invasive activity.
CONCLUSIONS: ECT2 cancer-testis antigen is likely to be a prognostic biomarker in clinic and a potential therapeutic target for the development of anticancer drugs and cancer vaccines for lung and esophageal cancers.

Salhia B, Tran NL, Chan A, et al.
The guanine nucleotide exchange factors trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma.
Am J Pathol. 2008; 173(6):1828-38 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
Malignant gliomas are characterized by their ability to invade normal brain tissue. We have previously shown that the small GTPase Rac1 plays a role in both migration and invasion in gliomas. Here, we aim to identify Rac-activating guanine nucleotide exchange factors (GEFs) that mediate glioblastoma invasiveness. Using a brain tumor expression database, we identified three GEFs, Trio, Ect2, and Vav3, that are expressed at higher levels in glioblastoma versus low-grade glioma. The expression of these GEFs is also associated with poor patient survival. Quantitative real-time polymerase chain reaction and immunohistochemical analyses on an independent set of tumors confirmed that these GEFs are overexpressed in glioblastoma as compared with either nonneoplastic brain or low-grade gliomas. In addition, depletion of Trio, Ect2, and Vav3 by siRNA oligonucleotides suppresses glioblastoma cell migration and invasion. Depletion of either Ect2 or Trio also reduces the rate of cell proliferation. These results suggest that targeting GEFs may present novel strategies for anti-invasive therapy for malignant gliomas.

Zhang ML, Lu S, Zhou L, Zheng SS
Correlation between ECT2 gene expression and methylation change of ECT2 promoter region in pancreatic cancer.
Hepatobiliary Pancreat Dis Int. 2008; 7(5):533-8 [PubMed] Related Publications
BACKGROUND: Pancreatic cancer is closely related to epigenetic abnormality. The epithelial cell transforming sequence 2 gene (ECT2) plays a critical role in Rho activation during cytokinesis, and thus may play a role in the pathogenesis of pancreatic cancer. In this study, we investigated the relationships between aberrant expression and epigenetic changes of the ECT2 gene in pancreatic cancer.
METHODS: Four cell lines (PANC-1, Colo357, T3M-4 and PancTuI) and pancreatic ductal adenocarcinoma (PDAC) tissues were used for mRNA detection. After restriction isoschizomer endonucleases (MspI/HpaII) were used to digest the DNA sequence (5'-CCGG-3'), PCR was made to amplify the product. And RT-PCR was applied to determine the expression of the gene.
RESULTS: The mRNA expression of the ECT2 gene was higher in pancreatic tumor tissue than in normal tissue. The gene was also expressed in the 4 PDAC cell lines. The methylation states of the upstream regions of the ECT2 gene were almost identical in normal, tumor pancreatic tissues, and the 4 PDAC cell lines. Some of the 5'-CCGG-3' areas in the upstream region of ECT2 were methylated, while others were unmethylated.
CONCLUSIONS: The oncogene ECT2 is overexpressed in pancreatic tumor tissues as verified by RT-PCR detection. The methylation status of DNA in promoter areas is involved in the gene expression, along with other factors, in pancreatic cancer.

Yang YL, Chu JY, Luo ML, et al.
Amplification of PRKCI, located in 3q26, is associated with lymph node metastasis in esophageal squamous cell carcinoma.
Genes Chromosomes Cancer. 2008; 47(2):127-36 [PubMed] Related Publications
DNA amplification is one of the mechanisms to activate genes that are implicated in neoplastic transformation and gain of chromosome band 3q26 is a common event in squamous cell carcinomas. The aim of the present work was to identify the specific target gene from four candidates (MDS1, PRKCI, ECT2, and PIK3CA) located on 3q26 amplification in esophageal squamous cell carcinomas (ESCCs). To assess the prevalence of copy number gains of putative genes, fluorescence in situ hybridization (FISH) was applied on 108 ESCCs and 9 ESCC cell lines. Our data showed that MDS1 and PRKCI were more frequently gained. Positive correlation was found only for PRKCI between amplification and tumor size (P = 0.043), lymph node metastasis (P = 0.015) and clinical stage (P = 0.002). PRKCI gene amplification was highly correlated with protein overexpression (P = 0.009), suggesting that gene amplification is one important mechanism involved in PRKCI overexpression. To investigate further the role of PRKCI alteration in esophageal tumors, a tissue microarray containing samples from 180 ESCCs was used for immunohistochemistry analysis. Statistical analysis revealed that PRKCI overexpression was correlated with lymph node metastasis (P = 0.002) and higher stage (P = 0.004). Performing multivariate logistic regression analysis, a significant association between PRKCI overexpression and presence of lymph node metastasis was found, which was independent of T-stage of the primary tumors (P = 0.004). Our results indicate that PRKCI is an attractive target in the 3q26 amplicon and that it may serve as a molecular marker for metastasis and occult advanced tumor stages in ESCC.

Sano M, Genkai N, Yajima N, et al.
Expression level of ECT2 proto-oncogene correlates with prognosis in glioma patients.
Oncol Rep. 2006; 16(5):1093-8 [PubMed] Related Publications
The ECT2 (epithelial cell transforming sequence 2) proto-oncogene encodes a guanine nucleotide exchange factor for Rho GTPases, and regulates cytokinesis. ECT2 plays a critical role in Rho activation during cytokinesis, and thus may play a role in the pathogenesis of glioma. In this study, we investigated relationships between ECT2 expression, tumor histology, and prognosis in glioma patients. ECT2 mRNA expression was examined using quantitative real-time PCR, while its protein expression was examined by immunohistochemistry of 54 glioma tissue samples. Expressions of ECT2 mRNA and protein were markedly increased in high-grade gliomas compared to low-grade gliomas. Patients in whom expression of ECT2 mRNA and protein in tumor tissues was the lowest survived longer than patients who had higher expression. In vitro, ECT2 siRNA inhibited glioma cell proliferation and invasion. These data suggest that increased expression of ECT2 contribute to promotion of tumor invasiveness and progression, implying that evaluation of ECT2 expression is a prognostic marker for glioma patients.

Roversi G, Pfundt R, Moroni RF, et al.
Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines.
Oncogene. 2006; 25(10):1571-83 [PubMed] Related Publications
Identification of genetic copy number changes in glial tumors is of importance in the context of improved/refined diagnostic, prognostic procedures and therapeutic decision-making. In order to detect recurrent genomic copy number changes that might play a role in glioma pathogenesis and/or progression, we characterized 25 primary glioma cell lines including 15 non glioblastoma (non GBM) (I-III WHO grade) and 10 GBM (IV WHO grade), by array comparative genomic hybridization, using a DNA microarray comprising approx. 3500 BACs covering the entire genome with a 1 Mb resolution and additional 800 BACs covering chromosome 19 at tiling path resolution. Combined evaluation by single clone and whole chromosome analysis plus 'moving average (MA) approach' enabled us to confirm most of the genetic abnormalities previously identified to be associated with glioma progression, including +1q32, +7, -10, -22q, PTEN and p16 loss, and to disclose new small genomic regions, some correlating with grade malignancy. Grade I-III gliomas exclusively showed losses at 3p26 (53%), 4q13-21 (33%) and 7p15-p21 (26%), whereas only GBMs exhibited 4p16.1 losses (40%). Other recurrent imbalances, such as losses at 4p15, 5q22-q23, 6p23-25, 12p13 and gains at 11p11-q13, were shared by different glioma grades. Three intervals with peak of loss could be further refined for chromosome 10 by our MA approach. Data analysis of full-coverage chromosome 19 highlighted two main regions of copy number gain, never described before in gliomas, at 19p13.11 and 19q13.13-13.2. The well-known 19q13.3 loss of heterozygosity area in gliomas was not frequently affected in our cell lines. Genomic hotspot detection facilitated the identification of small intervals resulting in positional candidate genes such as PRDM2 (1p36.21), LRP1B (2q22.3), ADARB2 (10p15.3), BCCIP (10q26.2) and ING1 (13q34) for losses and ECT2 (3q26.3), MDK, DDB2, IG20 (11p11.2) for gains. These data increase our current knowledge about cryptic genetic changes in gliomas and may facilitate the further identification of novel genetic elements, which may provide us with molecular tools for the improved diagnostics and therapeutic decision-making in these tumors.

Yen CC, Chen YJ, Pan CC, et al.
Copy number changes of target genes in chromosome 3q25.3-qter of esophageal squamous cell carcinoma: TP63 is amplified in early carcinogenesis but down-regulated as disease progressed.
World J Gastroenterol. 2005; 11(9):1267-72 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
AIM: By using comparative genomic hybridization, gain of 3q was found in 45-86% cases of esophageal squamous cell carcinoma (EC-SCC). Chromosome 3q25.3-qter is the minimal common region with several oncogenes found within this region. However, amplification patterns of these genes in EC-SCC have never been reported. The possible association of copy number changes of these genes with pathologic characteristics is still not clear.
METHODS: Real-time quantitative PCR (Q-PCR) was performed to analyze the copy number changes of 13 candidate genes within this region in 60 primary tumors of EC-SCC, and possible association of copy number changes with pathologic characteristics was analyzed by statistics. Immunohistochemistry (IHC) study was also performed on another set of 111 primary tumors of EC-SCC to verify the association between TP63 expression change and lymph node metastasis status.
RESULTS: The average copy numbers (+/-SE) per haploid genome of individual genes in 60 samples were (from centromere to telomere): SSR3: 4.19 (+/-0.69); CCNL1: 5.24 (+/-0.67); SMC4L1: 2.01 (+/-0.16); EVI1: 2.02 (+/-0.12); hTERC: 5.28 (+/-0.54); SKIL: 2.71 (+/-0.14); EIF5A2: 1.95 (+/-0.12); ECT2: 9.18 (+/-1.68); PIK3CA: 8.13 (+/-1.17); EIF4G1: 1.07 (+/-0.05); SST: 3.07 (+/-0.25); TP63: 2.51 (+/-0.22); TFRC: 2.42 (+/-0.19). Four clusters of amplification were found: SSR3 and CCLN1 at 3q25.31; hTERC and SKIL at 3q26.2; ECT2 and PIK3CA at 3q26.31-q26.32; and SST, TP63 and TFRC at 3q27.3-q29. Patients with lymph node metastasis had significantly lower copy number of TP63 in the primary tumor than those without lymph node metastasis. IHC study on tissue arrays also showed that patients with lymph node metastasis have significantly lower TP63 staining score in the primary tumor than those without lymph node metastasis.
CONCLUSION: This study showed that different amplification patterns were seen among different genes within 3q25.3-qter in EC-SCC, and several novel candidate oncogenes (SSR3, SMC4L1, ECT2, and SST) were identified. TP63 is amplified in early stage of EC-SCC carcinogenesis but down-regulated in advanced stage of disease.

Chan AM, Takai S, Yamada K, Miki T
Isolation of a novel oncogene, NET1, from neuroepithelioma cells by expression cDNA cloning.
Oncogene. 1996; 12(6):1259-66 [PubMed] Related Publications
We generated a cDNA expression library from a human neuroepithelioma cell line for detection of novel oncogenes by focus formation assay in NIH3T3 cells. A morphologically unique focus was identified upon transfection and the transforming plasmid was isolated. The transforming gene, designated NET1, encoded a predicted protein species of 54 kDa containing the Dbl-Homology (DH) motif. This motif is also present in other growth regulatory molecules including Bcr, Cdc24, Vav, Ras-Grf, Ect2, Ost, Tim and Tiam1, which have been implicated as regulators of small GTP-binding proteins. NIH3T3 cells transfected with NET1 expression plasmid showed altered growth properties in vitro and were tumorigenic when injected into nude mice. In addition, a 2.5 kb cDNA was isolated from a normal human cDNA library which represented the NET1 proto-oncogene contained a 5' extended open reading frame. The fact that the proto-oncogene failed to induce transformation in NIH3T3 cells suggested that the original NET1 oncogene was activated by 5'-truncation. The 3.0 and 2.4 kilobasepair (kb) transcripts of the NET1 gene was ubiquitously expressed in all tissues examined. Using fluorescence in situ hybridization, we localized the NET1 gene to the short arm of human chromosome 10 at band p15.

Chan AM, McGovern ES, Catalano G, et al.
Expression cDNA cloning of a novel oncogene with sequence similarity to regulators of small GTP-binding proteins.
Oncogene. 1994; 9(4):1057-63 [PubMed] Related Publications
We generated a cDNA expression library from a human mammary epithelial cell line for detection of novel oncogenes by focus formation assay in NIH3T3 cells. A morphologically unique focus was identified and the transforming plasmid was isolated. The transforming gene, designated TIM, encoded a predicted protein species of 60 kDa containing a Dbl-Homology (DH) motif. This motif is also present in other growth regulatory molecules including Bcr, Cdc24, Vav, Ras-grf, and Ect2 which have been implicated as regulators of small GTP-binding proteins. NIH3T3 cells transfected with TIM expression plasmid showed altered growth properties in vitro and were tumorigenic when injected into nude mice. The 6.5 kilobasepair (kb) transcript of the TIM gene was mainly expressed in kidney, liver, pancreas, lung, and placenta. By analysing a panel of human-hamster somatic cell hybrids, we localized the TIM gene to human chromosome 7.

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