Gene Summary

Gene:E2F4; E2F transcription factor 4
Aliases: E2F-4
Summary:The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses. The E2F proteins contain several evolutionally conserved domains found in most members of the family. These domains include a DNA binding domain, a dimerization domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids, and a tumor suppressor protein association domain which is embedded within the transactivation domain. This protein binds to all three of the tumor suppressor proteins pRB, p107 and p130, but with higher affinity to the last two. It plays an important role in the suppression of proliferation-associated genes, and its gene mutation and increased expression may be associated with human cancer. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor E2F4
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
Show (22)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 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.

  • Trans-Activators
  • Proto-Oncogene Proteins c-myc
  • Promoter Regions
  • Apoptosis
  • DNA-Binding Proteins
  • Transcription Factors
  • Protein Binding
  • Retinoblastoma-Like Protein p130
  • BCL2 protein
  • Microsatellite Repeats
  • Chromosome 16
  • Colorectal Cancer
  • Nuclear Proteins
  • Carrier Proteins
  • Immunohistochemistry
  • Repressor Proteins
  • Transforming Growth Factor beta Receptors
  • Cell Cycle
  • RB1
  • Neoplasm Proteins
  • Base Sequence
  • Proto-Oncogene Proteins
  • Gene Expression Profiling
  • Cancer Gene Expression Regulation
  • E2F Transcription Factors
  • Transcriptional Activation
  • E2F1
  • Binding Sites
  • Cell Proliferation
  • Protein-Serine-Threonine Kinases
  • Up-Regulation
  • Prostate Cancer
  • Breast Cancer
  • DNA Repair
  • Mutation
  • Down-Regulation
  • E2F4 Transcription Factor
  • Polymerase Chain Reaction
  • beta Catenin
  • Cell Cycle Proteins
Tag cloud generated 11 March, 2017 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: E2F4 (cancer-related)

Lee J, Jung JH, Chae YS, et al.
Long Noncoding RNA snaR Regulates Proliferation, Migration and Invasion of Triple-negative Breast Cancer Cells.
Anticancer Res. 2016; 36(12):6289-6295 [PubMed] Related Publications
AIM: We evaluated the role of long noncoding ribonucleic acid (lncRNA) in breast cancer cell lines by quantitative reverse transcription-polymerase change reaction.
MATERIALS AND METHODS: The effects of small NF90-associated RNA (snaR) with RNA interference on proliferation, migration and invasion of MDA-MB-231 cells were observed by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide, wound healing and transwell assay.
RESULTS: Among 90 lncRNAs, E2F transcription factor 4, p107/p130-binding (E2F4) antisense, insulin-like growth factor 2 antisense (IGF2AS), snaR, and small nucleolar RNA host gene 5 (SNHG5) were up-regulated in MDA-MB-231 and 7SK, antisense noncoding RNA in the INK4 locus (ANRIL), IGF2AS, Nespas, p53 mRNA, and snaR were up-regulated in MCF-7 cells. Down-regulation of snaR inhibited the proliferation, migration, and invasion of MDA-MD-231 breast cancer cells.
CONCLUSION: LncRNA snaR was found to be up-regulated in breast cancer cells, and the cancer progression of MDA-MB-231 cells was significantly suppressed by down-regulation of snaR. Therefore, snaR knockdown has potential as a treatment modality for triple-negative breast cancer.

Cheng C, Lou S, Andrews EH, et al.
Integrative Genomic Analyses Yield Cell-Cycle Regulatory Programs with Prognostic Value.
Mol Cancer Res. 2016; 14(4):332-43 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
UNLABELLED: Liposarcoma is the second most common form of sarcoma, which has been categorized into four molecular subtypes, which are associated with differential prognosis of patients. However, the transcriptional regulatory programs associated with distinct histologic and molecular subtypes of liposarcoma have not been investigated. This study uses integrative analyses to systematically define the transcriptional regulatory programs associated with liposarcoma. Likewise, computational methods are used to identify regulatory programs associated with different liposarcoma subtypes, as well as programs that are predictive of prognosis. Further analysis of curated gene sets was used to identify prognostic gene signatures. The integration of data from a variety of sources, including gene expression profiles, transcription factor-binding data from ChIP-Seq experiments, curated gene sets, and clinical information of patients, indicated discrete regulatory programs (e.g., controlled by E2F1 and E2F4), with significantly different regulatory activity in one or multiple subtypes of liposarcoma with respect to normal adipose tissue. These programs were also shown to be prognostic, wherein liposarcoma patients with higher E2F4 or E2F1 activity associated with unfavorable prognosis. A total of 259 gene sets were significantly associated with patient survival in liposarcoma, among which > 50% are involved in cell cycle and proliferation.
IMPLICATIONS: These integrative analyses provide a general framework that can be applied to investigate the mechanism and predict prognosis of different cancer types.

Fischer M, Quaas M, Nickel A, Engeland K
Indirect p53-dependent transcriptional repression of Survivin, CDC25C, and PLK1 genes requires the cyclin-dependent kinase inhibitor p21/CDKN1A and CDE/CHR promoter sites binding the DREAM complex.
Oncotarget. 2015; 6(39):41402-17 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The transcription factor p53 is central to cell cycle control by downregulation of cell cycle-promoting genes upon cell stress such as DNA damage. Survivin (BIRC5), CDC25C, and PLK1 encode important cell cycle regulators that are repressed following p53 activation. Here, we provide evidence that p53-dependent repression of these genes requires activation of p21 (CDKN1A, WAF1, CIP1). Chromatin immunoprecipitation (ChIP) data indicate that promoter binding of B-MYB switches to binding of E2F4 and p130 resulting in a replacement of the MMB (Myb-MuvB) by the DREAM complex. We demonstrate that this replacement depends on p21. Furthermore, transcriptional repression by p53 requires intact DREAM binding sites in the target promoters. The CDE and CHR cell cycle promoter elements are the sites for DREAM binding. These elements as well as the p53 response of Survivin, CDC25C, and PLK1 are evolutionarily conserved. No binding of p53 to these genes is detected by ChIP and mutation of proposed p53 binding sites does not alter the p53 response. Thus, a mechanism for direct p53-dependent transcriptional repression is not supported by the data. In contrast, repression by DREAM is consistent with most previous findings and unifies models based on p21-, E2F4-, p130-, and CDE/CHR-dependent repression by p53. In conclusion, the presented data suggest that the p53-p21-DREAM-CDE/CHR pathway regulates p53-dependent repression of Survivin, CDC25C, and PLK1.

Dodurga Y, Seçme M, Eroğlu C, et al.
Investigation of the effects of a sulfite molecule on human neuroblastoma cells via a novel oncogene URG4/URGCP.
Life Sci. 2015; 143:27-34 [PubMed] Related Publications
AIM: The aim of this study is to determine the anticancer effect of sulfite on SH-SY5Y neuroblastoma cells in vitro conditions and elucidate underlying molecular mechanism of sulfite and explore its therapeutic activity.
MAIN METHODS: In this study, cytotoxic effects of sulfite in SH-SY5Y cels were detected over time in a dose dependent manner with the IC50 doses ranging from 0.5 to 10 mM. Genotoxic effect of sulfite was shown by comet assay. IC50 doses in the SH-SY5Y cells were detected as 5 mM. Expression profiles of the target genes related to apoptosis and cell cycle control were determined by quantitative RT-PCR. Protein changes were determined by western blot analysis.
KEY FINDINGS: URG4/URGCP, CCND1, CCND2, CDK4, CDK6, E2F4 and BCL-2 gene expression levels were significantly reduced and RB1, TP53, BAX, BID, CASP2, CASP3, CASP9 and DIABLO gene expressions were significantly increased in dose group cells. The mechanism of this result may be related to sulfite dependent inhibition of cell cycle at the G1 phase by down-regulating URG4/URGCP or CCND1, CDK4, CDK6 gene expression and stimulating apoptosis via the intrinsic pathway. Sulfite suppressed invasion and colony formation in SH-SY5Y cell line using matrigel invasion chamber and colony formation assay, respectively.
SIGNIFICANCE: It is thought that sulfite demonstrates anticarcinogenesis activity by affecting cell cycle arrest, apoptosis s, invasion, and colony formation on SH-SY5Y cells. Sulfite may be an effective agent for treatment of neuroblastoma as a single agent or in combination with other agents.

Lawrenson K, Iversen ES, Tyrer J, et al.
Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer.
Carcinogenesis. 2015; 36(11):1341-53 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.

Gupta ED, Pachauri M, Ghosh PC, Rajam MV
Targeting polyamine biosynthetic pathway through RNAi causes the abrogation of MCF 7 breast cancer cell line.
Tumour Biol. 2016; 37(1):1159-71 [PubMed] Related Publications
The diamine putrescine and polyamines, spermidine (triamine) and spermine (tetraamine) are small organic polycations that play an indispensable role in key cellular processes such as the regulation of growth, differentiation, and macromolecular functions. Elevated levels of polyamines (PAs) have been shown to be one of the major factors involved in carcinogenesis. In this study, specific silencing of the expression of three genes of PA biosynthesis pathway, ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (SAMDC), and spermidine synthase (SPDSYN) was achieved using RNA interference in MCF 7 breast cancer cell line. For optimizing the effective small interfering nucleic acid (siNA), three variants of ODC siNA [siRNA, locked nucleic acid (LNA)-modified siRNA, and siHybrid (RNA and DNA hybrid)] were used and a dose- and time-dependent study was conducted. The PA biosynthetic genes were targeted individually and in combination. RNAi-mediated reduction in the expression of PA biosynthesis genes resulted in distorted cell morphology, reduced cancer cell viability, and migration characteristic. The most promising results were observed with the combined treatment of siSPDSYN and siODC with 83 % cell growth inhibition. On analyzing the messenger RNA (mRNA) expression profile of the cell cycle and apoptosis-related genes, it was observed that RNAi against PA biosynthetic genes downregulated the expression of CDK8, CCNE2, CCNH, CCNT1, CCNT2, CCNF, PCNA, CCND1, and CDK2, and upregulated the expression of E2F4, BAX, FAS, TP53, CDKN1A, BAK1, CDKN1B, ATM, GRANB, and ATR genes when compared with control-transfected cells. These results suggest that the targeting polyamine biosynthesis through RNAi approach could be a promising strategy for breast cancer therapy and might be extended for therapy of other cancers.

Altinoz MA, Tunalı NE
Trinucleotide repeat expansions in human breast cancer-susceptibility genes: relevant targets for aspirin chemoprevention?
Clin Transl Oncol. 2016; 18(1):9-17 [PubMed] Related Publications
PURPOSE: Defining novel molecular mechanisms pertinent to aspirin chemoprevention of breast cancer (BC) and to explain controversial epidemiological results in this regard.
METHODS: Literature search in relevant databases with the following key words; aspirin, nucleotide repeat expansions, breast cancer. Human genome contains nucleotide repeat expansions and exon-1 of the androgen receptor gene AR contains a CAG string with an average of 20 repeats. Longer AR CAG repeats associate with lower AR protein functioning leading relatively higher estrogen receptor signals and higher risk of hormone receptor-positive BC. Nucleotide repeat expansions also exist in E2F4 and POLG genes in BC. In cell culture models, aspirin reduces CAG.CTG expansions in kidney cells and restores myogenic differentiation in cells obtained from tissues with myotonic dystrophy, a disorder caused by large CTG expansions.
CONCLUSIONS: We hypothesize that aspirin reduction of trinucleotide repeat expansions in breast cancer-susceptibility genes may be one of the relevant mechanisms of its chemopreventive effects.

Diniz MG, Silva Jde F, de Souza FT, et al.
Association between cell cycle gene transcription and tumor size in oral squamous cell carcinoma.
Tumour Biol. 2015; 36(12):9717-22 [PubMed] Related Publications
Higher tumor size correlates with poor prognosis and is an independent predictive survival factor in oral squamous cell carcinoma (OSCC) patients. However, the molecular events underlining OSCC tumor evolution are poorly understood. We aimed to investigate if large OSCC tumors show different cell cycle gene transcriptional signature compared to small tumors. Seventeen fresh OSCC tumor samples with different tumor sizes (T) were included in the study. Tumors were from the tongue or from the floor of the mouth, and only three patients were nonsmokers. Samples were categorized according to clinical tumor size in tumors ≤2 cm (T1, n = 5) or tumors >2 cm (T2, n = 9; T3, n = 2; T4, n = 1). The group of tumors ≤2 cm was considered the reference group, while the larger tumors were considered the test group. We assessed the expression of 84 cell cycle genes by qRT-PCR array and normalized it to the expression of two housekeeping genes. Results were analyzed according to the formula 2(^-DeltaCt). A five-fold change cutoff was used, and p values <0.05 were considered statistically significant. Ki-67 immunohistochemistry was performed to estimate cell proliferation index. Twenty-nine genes were downregulated in the test group (larger tumors) compared to the reference group (smaller tumors). Among these genes, 13 reached statistical significance: ANAPC4, CUL1, SUMO1, KPNA2, MAD2L2, CCNG2, E2F4, NBN, CUL2, PCNA, TFDP1, KNTC1, and ATR. Ki-67 labeling index was similar in both tumor groups. Our findings suggest that the transcriptional activity of specific cell cycle genes varies according to the size of OSCC tumor, which probably reflects tumor molecular evolution and adaptation to the microenvironment.

Eroğlu C, Seçme M, Bağcı G, Dodurga Y
Assessment of the anticancer mechanism of ferulic acid via cell cycle and apoptotic pathways in human prostate cancer cell lines.
Tumour Biol. 2015; 36(12):9437-46 [PubMed] Related Publications
Studies on genetic changes underlying prostate cancer and the possible signaling pathways are getting increased day by day, and new treatment methods are being searched for. The aim of the present study is to investigate the effects of ferulic acid (FA), a phenolic compound, on cell cycle, apoptosis, invasion, and colony formation in the PC-3 and LNCaP prostate cancer cells. The effect of FA on cell viability was determined via a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) method. Total RNA was isolated with Tri Reagent. Expression of 84 genes for both cell cycle and apoptosis separately was evaluated by reverse transcriptase PCR (RT-PCR). Protein expressions were evaluated by Western blot analysis. Furthermore, apoptotic effects of FA were observed with terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) assay. Effects of FA on cell invasion and colony formation were determined using Matrigel chamber and colony assay, respectively. The half maximal inhibitory concentration (IC50) dose of FA was found to be 300 μM in PC-3 cells and 500 μM in LNCaP cells. According to RT-PCR results, it was observed that FA inhibited cell proliferation by increasing the gene expressions of ATR, ATM, CDKN1A, CDKN1B, E2F4, RB1, and TP53 and decreasing the gene expressions of CCND1, CCND2, CCND3, CDK2, CDK4, and CDK6 in PC-3 cells. On the other hand, it was seen that FA suppressed cell proliferation by increasing in the gene expressions of CASP1, CASP2, CASP8, CYCS, FAS, FASLG, and TRADD and decreasing in the gene expressions of BCL2 and XIAP in LNCaP cells. In this study, protein expression of CDK4 and BCL2 genes significantly decreased in these cells. It could induce apoptosis in PC-3 and LNCaP cells. Also, it was observed that FA suppressed the invasion in PC-3 and LNCaP cells. Moreover, it suppressed the colony formation. In conclusion, it has been observed that FA may lead to cell cycle arrest in PC-3 cells while it may cause apoptosis in LNCaP cells.

Ruppender N, Larson S, Lakely B, et al.
Cellular Adhesion Promotes Prostate Cancer Cells Escape from Dormancy.
PLoS One. 2015; 10(6):e0130565 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Dissemination of prostate cancer (PCa) cells to the bone marrow is an early event in the disease process. In some patients, disseminated tumor cells (DTC) proliferate to form active metastases after a prolonged period of undetectable disease known as tumor dormancy. Identifying mechanisms of PCa dormancy and reactivation remain a challenge partly due to the lack of in vitro models. Here, we characterized in vitro PCa dormancy-reactivation by inducing cells from three patient-derived xenograft (PDX) lines to proliferate through tumor cell contact with each other and with bone marrow stroma. Proliferating PCa cells demonstrated tumor cell-cell contact and integrin clustering by immunofluorescence. Global gene expression analyses on proliferating cells cultured on bone marrow stroma revealed a downregulation of TGFB2 in all of the three proliferating PCa PDX lines when compared to their non-proliferating counterparts. Furthermore, constitutive activation of myosin light chain kinase (MLCK), a downstream effector of integrin-beta1 and TGF-beta2, in non-proliferating cells promoted cell proliferation. This cell proliferation was associated with an upregulation of CDK6 and a downregulation of E2F4. Taken together, our data provide the first clinically relevant in vitro model to support cellular adhesion and downregulation of TGFB2 as a potential mechanism by which PCa cells may escape from dormancy. Targeting the TGF-beta2-associated mechanism could provide novel opportunities to prevent lethal PCa metastasis.

Park SA, Platt J, Lee JW, et al.
E2F8 as a Novel Therapeutic Target for Lung Cancer.
J Natl Cancer Inst. 2015; 107(9) [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: The E2F members have been divided into transcription activators (E2F1-E2F3) and repressors (E2F4-E2F8). E2F8 with E2F7 has been known to play an important physiologic role in embryonic development and cell cycle regulation by repressing E2F1. However, the function of E2F8 in cancer cells is unknown.
METHODS: E2F8 expression was assessed by immunoblotting or immunofluorescence staining in human lung cancer (LC) cells and tissues from LC patients (n = 45). Cell proliferation, colony formation, and invasion analysis were performed to evaluate the role of E2F8 in LC. Microarray analysis was used to determine the target genes of E2F8. The regulation of E2F8 on the expression of ubiquitin-like PHD and RING domain-containing 1 (UHRF1), one of E2F8 target genes, was determined using chromatin immunoprecipitation and promoter activity assays. Human LC xenograft models were used to determine the effects of inhibiting E2F8 by siRNAs (n = 7 per group) or antisense morpholino (n = 8 per group) on tumor growth. Survival was analyzed using the Kaplan-Meier method and group differences by the Student's t test. All statistical tests were two-sided.
RESULTS: LC tumors overexpressed E2F8 compared with normal lung tissues. Depletion of E2F8 inhibited cell proliferation and tumor growth. E2F8 knockdown statistically significantly reduced the expression of UHRF1 (~60%-70%, P < .001), and the direct binding of E2F8 on the promoter of UHRF1 was identified. Kaplan-Meier analysis with a public database showed prognostic significance of aberrant E2F8 expression in LC (HR = 1.91 95% CI = 1.21 to 3.01 in chemo-naïve patients, P = .0047).
CONCLUSIONS: We demonstrated that E2F8 is overexpressed in LC and is required for the growth of LC cells. These findings implicate E2F8 as a novel therapeutic target for LC treatment.

Cheng C, Varn FS, Marsit CJ
E2F4 Program Is Predictive of Progression and Intravesical Immunotherapy Efficacy in Bladder Cancer.
Mol Cancer Res. 2015; 13(9):1316-24 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
UNLABELLED: Bladder cancer is a common malignant disease, with non-muscle-invasive bladder cancer (NMIBC) representing the majority of tumors. This cancer subtype is typically treated by transurethral resection. In spite of treatment, up to 70% of patients show local recurrences. Intravesical BCG (Bacillus Calmette-Guerin) immunotherapy has been widely used to treat NMIBC, but it fails to suppress recurrence of bladder tumors in up to 40% of patients. Therefore, the development of prognostic markers is needed to predict the progression of bladder cancer and the efficacy of intravesical BCG treatment. This study demonstrates the effectiveness of an E2F4 signature for prognostic prediction of bladder cancer. E2F4 scores for each sample in a bladder cancer expression dataset were calculated by summarizing the relative expression levels of E2F4 target genes identified by ChIP-seq, and then the scores were used to stratify patients into good- and poor-outcome groups. The molecular signature was investigated in a single bladder cancer dataset and then its effectiveness was confirmed in two meta-bladder datasets consisting of specimens from multiple independent studies. These results were consistent in different datasets and demonstrate that the E2F4 score is predictive of clinical outcomes in bladder cancer, with patients whose tumors exhibit an E2F4 score >0 having significantly shorter survival times than those with an E2F4 score <0, in both non-muscle-invasive, and muscle-invasive bladder cancer. Furthermore, although intravesical BCG immunotherapy can significantly improve the clinical outcome of NMIBC patients with positive E2F4 scores (E2F4>0 group), it does not show significant treatment effect for those with negative scores (E2F4<0 group).
IMPLICATIONS: The E2F4 signature can be applied to predict the progression/recurrence and the responsiveness of patients to intravesical BCG immunotherapy in bladder cancer.

Schwentner R, Papamarkou T, Kauer MO, et al.
EWS-FLI1 employs an E2F switch to drive target gene expression.
Nucleic Acids Res. 2015; 43(5):2780-9 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Cell cycle progression is orchestrated by E2F factors. We previously reported that in ETS-driven cancers of the bone and prostate, activating E2F3 cooperates with ETS on target promoters. The mechanism of target co-regulation remained unknown. Using RNAi and time-resolved chromatin-immunoprecipitation in Ewing sarcoma we report replacement of E2F3/pRB by constitutively expressed repressive E2F4/p130 complexes on target genes upon EWS-FLI1 modulation. Using mathematical modeling we interrogated four alternative explanatory models for the observed EWS-FLI1/E2F3 cooperation based on longitudinal E2F target and regulating transcription factor expression analysis. Bayesian model selection revealed the formation of a synergistic complex between EWS-FLI1 and E2F3 as the by far most likely mechanism explaining the observed kinetics of E2F target induction. Consequently we propose that aberrant cell cycle activation in Ewing sarcoma is due to the de-repression of E2F targets as a consequence of transcriptional induction and physical recruitment of E2F3 by EWS-FLI1 replacing E2F4 on their target promoters.

Valenti F, Ganci F, Fontemaggi G, et al.
Gain of function mutant p53 proteins cooperate with E2F4 to transcriptionally downregulate RAD17 and BRCA1 gene expression.
Oncotarget. 2015; 6(8):5547-66 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Genomic instability (IN) is a common feature of many human cancers. The TP53 tumour suppressor gene is mutated in approximately half of human cancers. Here, we show that BRCA1 and RAD17 genes, whose derived proteins play a pivotal role in DNA damage repair, are transcriptional targets of gain-of-function mutant p53 proteins. Indeed, high levels of mutp53 protein facilitate DNA damage accumulation and severely impair BRCA1 and RAD17 expression in proliferating cancer cells. The recruitment of mutp53/E2F4 complex onto specific regions of BRCA1 and RAD17 promoters leads to the inhibition of their expression. BRCA1 and RAD17 mRNA expression is reduced in HNSCC patients carrying TP53 mutations when compared to those bearing wt-p53 gene. Furthermore, the analysis of gene expression databases for breast cancer patients reveals that low expression of DNA repair genes correlates significantly with reduced relapse free survival of patients carrying TP53 gene mutations. Collectively, these findings highlight the direct involvement of transcriptionally active gain of function mutant p53 proteins in genomic instability through the impairment of DNA repair mechanisms.

Khaleel SS, Andrews EH, Ung M, et al.
E2F4 regulatory program predicts patient survival prognosis in breast cancer.
Breast Cancer Res. 2014; 16(6):486 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
INTRODUCTION: Genetic and molecular signatures have been incorporated into cancer prognosis prediction and treatment decisions with good success over the past decade. Clinically, these signatures are usually used in early-stage cancers to evaluate whether they require adjuvant therapy following surgical resection. A molecular signature that is prognostic across more clinical contexts would be a useful addition to current signatures.
METHODS: We defined a signature for the ubiquitous tissue factor, E2F4, based on its shared target genes in multiple tissues. These target genes were identified by chromatin immunoprecipitation sequencing (ChIP-seq) experiments using a probabilistic method. We then computationally calculated the regulatory activity score (RAS) of E2F4 in cancer tissues, and examined how E2F4 RAS correlates with patient survival.
RESULTS: Genes in our E2F4 signature were 21-fold more likely to be correlated with breast cancer patient survival time compared to randomly selected genes. Using eight independent breast cancer datasets containing over 1,900 unique samples, we stratified patients into low and high E2F4 RAS groups. E2F4 activity stratification was highly predictive of patient outcome, and our results remained robust even when controlling for many factors including patient age, tumor size, grade, estrogen receptor (ER) status, lymph node (LN) status, whether the patient received adjuvant therapy, and the patient's other prognostic indices such as Adjuvant! and the Nottingham Prognostic Index scores. Furthermore, the fractions of samples with positive E2F4 RAS vary in different intrinsic breast cancer subtypes, consistent with the different survival profiles of these subtypes.
CONCLUSIONS: We defined a prognostic signature, the E2F4 regulatory activity score, and showed it to be significantly predictive of patient outcome in breast cancer regardless of treatment status and the states of many other clinicopathological variables. It can be used in conjunction with other breast cancer classification methods such as Oncotype DX to improve clinical outcome prediction.

Wissing ML, Sonne SB, Westergaard D, et al.
The transcriptome of corona radiata cells from individual MІІ oocytes that after ICSI developed to embryos selected for transfer: PCOS women compared to healthy women.
J Ovarian Res. 2014; 7:110 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Corona radiata cells (CRCs) refer to the fraction of cumulus cells just adjacent to the oocyte. The CRCs are closely connected to the oocyte throughout maturation and their gene expression profiles might reflect oocyte quality. Polycystic ovary syndrome (PCOS) is a common cause of infertility. It is controversial whether PCOS associate with diminished oocyte quality. The purpose of this study was to compare individual human CRC samples between PCOS patients and controls.
METHODS: All patients were stimulated by the long gonadotropin-releasing hormone (GnRH) agonist protocol. The CRC samples originated from individual oocytes developing into embryos selected for transfer. CRCs were isolated in a two-step denudation procedure, separating outer cumulus cells from the inner CRCs. Extracted RNA was amplified and transcriptome profiling was performed with Human Agilent® arrays.
RESULTS: The transcriptomes of CRCs showed no individual genes with significant differential expression between PCOS and controls, but gene set enrichment analysis identified several cell cycle- and DNA replication pathways overexpressed in PCOS CRCs (FDR < 0.05). Five of the genes contributing to the up-regulated cell cycle pathways in the PCOS CRCs were selected for qRT-PCR validation in ten PCOS and ten control CRC samples. qRT-PCR confirmed significant up-regulation in PCOS CRCs of cell cycle progression genes HIST1H4C (FC = 2.7), UBE2C (FC = 2.6) and cell cycle related transcription factor E2F4 (FC = 2.5).
CONCLUSION: The overexpression of cell cycle-related genes and cell cycle pathways in PCOS CRCs could indicate a disturbed or delayed final maturation and differentiation of the CRCs in response to the human chorionic gonadotropin (hCG) surge. However, this had no effect on the in vitro development of the corresponding embryos. Future studies are needed to clarify whether the up-regulated cell cycle pathways in PCOS CRCs have any clinical implications.

Cito L, Indovina P, Forte IM, et al.
pRb2/p130 localizes to the cytoplasm in diffuse gastric cancer.
J Cell Physiol. 2015; 230(4):802-5 [PubMed] Related Publications
pRb2/p130 is a key tumor suppressor, whose oncosuppressive activity has mainly been attributed to its ability to negatively regulate cell cycle by interacting with the E2F4 and E2F5 transcription factors. Indeed, pRb2/p130 has been found altered in various cancer types in which it functions as a valuable prognostic marker. Here, we analyzed pRb2/p130 expression in gastric cancer tissue samples of diffuse histotype, in comparison with their normal counterparts. We found a cytoplasmic localization of pRb2/p130 in cancer tissue samples, whereas, in normal counterparts, we observed the expected nuclear localization. pRb2/p130 cytoplasmic delocalization can lead to cell cycle deregulation, but considering the emerging involvement of pRb2/p130 in other key cellular processes, it could contribute to gastric tumorigenesis also through other mechanisms. Our data support the necessity of further investigations to verify the possibility of using pRb2/p130 as a biomarker or potential therapeutic target for diffuse gastric cancer.

He WL, Li YH, Hou WJ, et al.
RAD51 potentiates synergistic effects of chemotherapy with PCI-24781 and cis-diamminedichloroplatinum on gastric cancer.
World J Gastroenterol. 2014; 20(29):10094-107 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
AIM: To explore the efficacy of PCI-24781, a broad-spectrum, hydroxamic acid-derived histone deacetylase inhibitor, in the treatment of gastric cancer (GC).
METHODS: With or without treatment of PCI-24781 and/or cis-diamminedichloroplatinum (CDDP), GC cell lines were subjected to functional analysis, including cell growth, apoptosis and clonogenic assays. Chromatin immunoprecipitation and luciferase reporter assays were used to determine the interacting molecules and the activity of the enzyme. An in vivo study was carried out in GC xenograft mice. Cell culture-based assays were represented as mean ± SD. ANOVA tests were used to assess differences across groups. All pairwise comparisons between tumor weights among treatment groups were made using the Tukey-Kramer method for multiple comparison adjustment to control experimental-wise type I error rates. Significance was set at P < 0.05.
RESULTS: PCI-24781 significantly reduced the growth of the GC cells, enhanced cell apoptosis and suppressed clonogenicity, and these effects synergized with the effects of CDDP. PCI-24781 modulated the cell cycle and significantly reduced the expression of RAD51, which is related to homologous recombination. Depletion of RAD51 augmented the biological functions of PCI-24781, CDDP and the combination treatment, whereas overexpressing RAD51 had the opposite effects. Increased binding of the transcription suppressor E2F4 on the RAD51 promoter appeared to play a major role in these processes. Furthermore, significant suppression of tumor growth and weight in vivo was obtained following PCI-24781 treatment, which synergized with the anticancer effect of CDDP.
CONCLUSION: These data suggest that RAD51 potentiates the synergistic effects of chemotherapy with PCI-24781 and CDDP on GC.

Baiz D, Dapas B, Farra R, et al.
Bortezomib effect on E2F and cyclin family members in human hepatocellular carcinoma cell lines.
World J Gastroenterol. 2014; 20(3):795-803 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
AIM: To evaluate the effects of the proteasome inhibitor bortezomib (BZB) on E2Fs and related genes in hepatocellular carcinoma (HCC) cells.
METHODS: The mRNA levels of the E2F family members (pro-proliferative: E2F1-3 and anti-proliferative: E2F4-8) and of their related genes cyclins and cyclin-dependent kinases (cdks) were evaluated in two HCC cell lines following a single BZB administration. mRNA levels of the epithelial-mesenchymal transition (EMT) genes were also measured in both cell lines after BZB treatment. The BZB concentration (40 nmol/L) used was chosen to stay well below the maximal amount/cm² recommended for in vivo application, and 2 d incubation was chosen as this time point has been found optimal to detect BZB effects in our previous studies. The HCC cell lines, HepG2 and JHH6, were chosen as they display different phenotypes, hepatocyte-like for HepG2 and undifferentiated for JHH6, thus representing an in vitro model of low and high aggressive forms of HCC, respectively. The mRNA levels of the target genes were measured by two-color microarray-based gene expression analysis, performed according to Agilent Technologies protocol and using an Agilent Scan B. For the E2F family members, mRNA levels were quantified by real-time reverse transcription polymerase chain reaction (RT-PCR). Using small interfering RNA's, the effects of E2F8 depletion on cell number was also evaluated.
RESULTS: After BZB treatment, microarray analysis of the undifferentiated JHH6 revealed a significant decrease in the expression of the pro-proliferative E2F member E2F2. Quantitative RT-PCR data were in keeping with the microarray analysis, and showed a significant increase and decrease in E2F8 and E2F2 mRNA levels, respectively. In contrast, BZB treatment of the hepatocyte-like HCC cell line HepG2 had a significant impact on mRNA levels of 5 of the 8 E2F members. In particular, mRNA levels of the pro-proliferative E2F members E2F1, E2F2, and of the anti-proliferative member E2F8, decreased over 80%. Notably, a reduction in E2F8 expression in HepG2 and JHH6 cells following siRNA treatment had no impact on cell proliferation. As observed with JHH6, BZB treatment of HepG2 cells induced a significant increase in mRNA levels of an anti-proliferative E2F member, E2F6 in this case. As was observed with E2F's, more dramatic changes in mRNA levels of the E2F related genes cyclins and Cdks and EMT genes were observed after BZB treatment of HepG2 compared to JHH6.
CONCLUSION: The differential expression of E2Fs and related genes induced by BZB in diverse HCC cell phenotypes contribute to bortezomib's mechanism of action in hepatocellular carcinoma.

Liu Y, Tennant DA, Zhu Z, et al.
DiME: a scalable disease module identification algorithm with application to glioma progression.
PLoS One. 2014; 9(2):e86693 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Disease module is a group of molecular components that interact intensively in the disease specific biological network. Since the connectivity and activity of disease modules may shed light on the molecular mechanisms of pathogenesis and disease progression, their identification becomes one of the most important challenges in network medicine, an emerging paradigm to study complex human disease. This paper proposes a novel algorithm, DiME (Disease Module Extraction), to identify putative disease modules from biological networks. We have developed novel heuristics to optimise Community Extraction, a module criterion originally proposed for social network analysis, to extract topological core modules from biological networks as putative disease modules. In addition, we have incorporated a statistical significance measure, B-score, to evaluate the quality of extracted modules. As an application to complex diseases, we have employed DiME to investigate the molecular mechanisms that underpin the progression of glioma, the most common type of brain tumour. We have built low (grade II)--and high (GBM)--grade glioma co-expression networks from three independent datasets and then applied DiME to extract potential disease modules from both networks for comparison. Examination of the interconnectivity of the identified modules have revealed changes in topology and module activity (expression) between low- and high- grade tumours, which are characteristic of the major shifts in the constitution and physiology of tumour cells during glioma progression. Our results suggest that transcription factors E2F4, AR and ETS1 are potential key regulators in tumour progression. Our DiME compiled software, R/C++ source code, sample data and a tutorial are available at http://www.cs.bham.ac.uk/~szh/DiME.

Paquin MC, Leblanc C, Lemieux E, et al.
Functional impact of colorectal cancer-associated mutations in the transcription factor E2F4.
Int J Oncol. 2013; 43(6):2015-22 [PubMed] Related Publications
The transcription factor E2F4 plays a critical role in cell cycle progression of normal and cancerous intestinal epithelial cells. Contrary to other E2Fs, the coding region of the E2F4 gene contains a longer spacer segment of a CAG trinucleotide repeat sequence encoding 13 consecutive serine residues, which is highly vulnerable to frameshift mutations in situations of genetic instability. Mutations in this region of the E2F4 gene have been observed in colorectal tumors with microsatellite instability. However, the effect of these changes on its function in colorectal cancer cells is currently unknown. We generated E2F4(CAG)₁₂ and E2F4(CAG)₁₄ mutants and compared their activity to the E2F4 wild-type, E2F4(CAG)₁₃. Luciferase assays with the thymidine kinase-luc reporter gene revealed that the mutants were more transcriptionally active than wild-type E2F4. The mechanism of increased activity of E2F4 was primarily related to protein stability, due to a significantly enhanced half-life of E2F4 mutants comparatively to that of wild-type E2F4. However, the association with the pocket protein p130/RBL2 did not account for this increased protein stability. Sequencing analysis of the endogenous E2F4 gene in a series of colorectal cancer cell lines showed that the microsatellite-unstable cell line SW48 exhibited a serine deletion in this gene. Accordingly, E2F4 half-life was much more elevated in SW48 cells in comparison to Caco-2/15, a microsatellite-stable cell line. Notably, in soft-agar assays, both mutants more potently increased anchorage-independent growth in comparison to wild-type E2F4. In conclusion, our data demonstrate that cancer-associated E2F4 mutations enhance the capacity of colorectal cancer cells to grow without anchorage, thereby contributing to tumor progression.

Poos K, Smida J, Nathrath M, et al.
How microRNA and transcription factor co-regulatory networks affect osteosarcoma cell proliferation.
PLoS Comput Biol. 2013; 9(8):e1003210 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Osteosarcomas (OS) are complex bone tumors with various genomic alterations. These alterations affect the expression and function of several genes due to drastic changes in the underlying gene regulatory network. However, we know little about critical gene regulators and their functional consequences on the pathogenesis of OS. Therefore, we aimed to determine microRNA and transcription factor (TF) co-regulatory networks in OS cell proliferation. Cell proliferation is an essential part in the pathogenesis of OS and deeper understanding of its regulation might help to identify potential therapeutic targets. Based on expression data of OS cell lines divided according to their proliferative activity, we obtained 12 proliferation-related microRNAs and corresponding target genes. Therewith, microRNA and TF co-regulatory networks were generated and analyzed regarding their structure and functional influence. We identified key co-regulators comprising the microRNAs miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC in the derived networks. These regulators are implicated in NFKB- and RB1-signaling and focal adhesion processes based on their common or interacting target genes (e.g., CDK6, CTNNB1, E2F4, HES1, ITGA6, NFKB1, NOTCH1, and SIN3A). Thus, we proposed a model of OS cell proliferation which is primarily co-regulated through the interactions of the mentioned microRNA and TF combinations. This study illustrates the benefit of systems biological approaches in the analysis of complex diseases. We integrated experimental data with publicly available information to unravel the coordinated (post)-transcriptional control of microRNAs and TFs to identify potential therapeutic targets in OS. The resulting microRNA and TF co-regulatory networks are publicly available for further exploration to generate or evaluate own hypotheses of the pathogenesis of OS (http://www.complex-systems.uni-muenster.de/co_networks.html).

Paquin MC, Cagnol S, Carrier JC, et al.
ERK-associated changes in E2F4 phosphorylation, localization and transcriptional activity during mitogenic stimulation in human intestinal epithelial crypt cells.
BMC Cell Biol. 2013; 14:33 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: The transcription factor E2F4 controls proliferation of normal and cancerous intestinal epithelial cells. E2F4 localization in normal human intestinal epithelial cells (HIEC) is cell cycle-dependent, being cytoplasmic in quiescent differentiated cells but nuclear in proliferative cells. However, the intracellular signaling mechanisms regulating such E2F4 localization remain unknown.
RESULTS: Treatment of quiescent HIEC with serum induced ERK1/2 activation, E2F4 phosphorylation, E2F4 nuclear translocation and G1/S phase transition while inhibition of MEK/ERK signaling by U0126 prevented these events. Stimulation of HIEC with epidermal growth factor (EGF) also led to the activation of ERK1/2 but, in contrast to serum or lysophosphatidic acid (LPA), EGF failed to induce E2F4 phosphorylation, E2F4 nuclear translocation and G1/S phase transition. Furthermore, Akt and GSK3β phosphorylation levels were markedly enhanced in serum- or LPA-stimulated HIEC but not by EGF. Importantly, E2F4 phosphorylation, E2F4 nuclear translocation and G1/S phase transition were all observed in response to EGF when GSK3 activity was concomitantly inhibited by SB216763. Finally, E2F4 was found to be overexpressed, phosphorylated and nuclear localized in epithelial cells from human colorectal adenomas exhibiting mutations in APC and KRAS or BRAF genes, known to deregulate GSK3/β-catenin and MEK/ERK signaling, respectively.
CONCLUSIONS: The present results indicate that MEK/ERK activation and GSK3 inhibition are both required for E2F4 phosphorylation as well as its nuclear translocation and S phase entry in HIEC. This finding suggests that dysregulated E2F4 nuclear localization may be an instigating event leading to hyperproliferation and hence, of tumor initiation and promotion in the colon and rectum.

Kurimchak A, Haines DS, Garriga J, et al.
Activation of p107 by fibroblast growth factor, which is essential for chondrocyte cell cycle exit, is mediated by the protein phosphatase 2A/B55α holoenzyme.
Mol Cell Biol. 2013; 33(16):3330-42 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The phosphorylation state of pocket proteins during the cell cycle is determined at least in part by an equilibrium between inducible cyclin-dependent kinases (CDKs) and serine/threonine protein phosphatase 2A (PP2A). Two trimeric holoenzymes consisting of the core PP2A catalytic/scaffold dimer and either the B55α or PR70 regulatory subunit have been implicated in the activation of p107/p130 and pRB, respectively. While the phosphorylation state of p107 is very sensitive to forced changes of B55α levels in human cell lines, regulation of p107 in response to physiological modulation of PP2A/B55α has not been elucidated. Here we show that fibroblast growth factor 1 (FGF1), which induces maturation and cell cycle exit in chondrocytes, triggers rapid accumulation of p107-PP2A/B55α complexes coinciding with p107 dephosphorylation. Reciprocal solution-based mass spectrometric analysis identified the PP2A/B55α complex as a major component in p107 complexes, which also contain E2F/DPs, DREAM subunits, and/or cyclin/CDK complexes. Of note, p107 is one of the preferred partners of B55α, which also associates with pRB in RCS cells. FGF1-induced dephosphorylation of p107 results in its rapid accumulation in the nucleus and formation of larger complexes containing p107 and enhances its interaction with E2F4 and other p107 partners. Consistent with a key role of B55α in the rapid activation of p107 in chondrocytes, limited ectopic expression of B55α results in marked dephosphorylation of p107 while B55α knockdown results in hyperphosphorylation. More importantly, knockdown of B55α dramatically delays FGF1-induced dephosphorylation of p107 and slows down cell cycle exit. Moreover, dephosphorylation of p107 in response to FGF1 treatment results in early recruitment of p107 to the MYC promoter, an FGF1/E2F-regulated gene. Our results suggest a model in which FGF1 mediates rapid dephosphorylation and activation of p107 independently of the CDK activities that maintain p130 and pRB hyperphosphorylation for several hours after p107 dephosphorylation in maturing chondrocytes.

Bultmann I, Conradi A, Kretschmer C, Sterner-Kock A
Latent transforming growth factor β-binding protein 4 is downregulated in esophageal cancer via promoter methylation.
PLoS One. 2013; 8(5):e65614 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Latent transforming growth factor β-binding protein 4 (LTBP4) is an extracellular matrix molecule that is a member of important connective tissue networks and is needed for the correct folding and the secretion of TGF-β1. LTBP4 is downregulated in carcinomas of various tissues. Here we show that LTBP4 is also downregulated in adenocarcinomas and squamous cell carcinomas of the esophagus in vitro and in vivo. Re-expression of LTBP4 in esophageal cancer cell lines reduced cell migration ability, whereas cell viability and cell proliferation remained unchanged. Hypermethylation of the promoter regions of the two main human LTBP4 transcriptional forms, LTBP4L and LTBP4S, was found to be involved in LTBP4 silencing. Detailed investigations of the methylation patterns of the promoter regions of LTBP4L and LTBP4S identified GATA1, SP1, E2F4 and SMAD3 as potential transcription factors involved in LTBP4 expression. In in vitro transcription factor activity studies we discovered E2F4 as novel powerful regulator for LTBP4S expression.

López-Díaz FJ, Gascard P, Balakrishnan SK, et al.
Coordinate transcriptional and translational repression of p53 by TGF-β1 impairs the stress response.
Mol Cell. 2013; 50(4):552-64 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Cellular stress results in profound changes in RNA and protein synthesis. How cells integrate this intrinsic, p53-centered program with extracellular signals is largely unknown. We demonstrate that TGF-β1 signaling interferes with the stress response through coordinate transcriptional and translational repression of p53 levels, which reduces p53-activated transcription, and apoptosis in precancerous cells. Mechanistically, E2F-4 binds constitutively to the TP53 gene and induces transcription. TGF-β1-activated Smads are recruited to a composite Smad/E2F-4 element by an E2F-4/p107 complex that switches to a Smad corepressor, which represses TP53 transcription. TGF-β1 also causes dissociation of ribosomal protein RPL26 and elongation factor eEF1A from p53 mRNA, thereby reducing p53 mRNA association with polyribosomes and p53 translation. TGF-β1 signaling is dominant over stress-induced transcription and translation of p53 and prevents stress-imposed downregulation of Smad proteins. Thus, crosstalk between the TGF-β and p53 pathways defines a major node of regulation in the cellular stress response, enhancing drug resistance.

Luo C, Sheng J, Hu MG, et al.
Loss of ARF sensitizes transgenic BRAFV600E mice to UV-induced melanoma via suppression of XPC.
Cancer Res. 2013; 73(14):4337-48 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Both genetic mutations and UV irradiation (UVR) can predispose individuals to melanoma. Although BRAF(V600E) is the most prevalent oncogene in melanoma, the BRAF(V600E) mutant is not sufficient to induce tumors in vivo. Mutation at the CDKN2A locus is another melanoma-predisposing event that can disrupt the function of both p16(INK4a) and ARF. Numerous studies have focused on the role of p16(INK4a) in melanoma, but the involvement of ARF, a well-known p53 activator, is still controversial. Using a transgenic BRAF(V600E) mouse model previously generated in our laboratory, we report that loss of ARF is able to enhance spontaneous melanoma formation and cause profound sensitivity to neonatal UVB exposure. Mechanistically, BRAF(V600E) and ARF deletion synergize to inhibit nucleotide excision repair by epigenetically repressing XPC and inhibiting the E2F4/DP1 complex. We suggest that the deletion of ARF promotes melanomagenesis not by abrogating p53 activation but by acting in concert with BRAF(V600E) to increase the load of DNA damage caused by UVR.

Yong KJ, Milenic DE, Baidoo KE, Brechbiel MW
212Pb-radioimmunotherapy potentiates paclitaxel-induced cell killing efficacy by perturbing the mitotic spindle checkpoint.
Br J Cancer. 2013; 108(10):2013-20 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Paclitaxel has recently been reported by this laboratory to potentiate the high-LET radiation therapeutic (212)Pb-TCMC-trastuzumab, which targets HER2. To elucidate mechanisms associated with this therapy, targeted α-particle radiation therapeutic (212)Pb-TCMC-trastuzumab together with paclitaxel was investigated for the treatment of disseminated peritoneal cancers.
METHODS: Mice bearing human colon cancer LS-174T intraperitoneal xenografts were pre-treated with paclitaxel, followed by treatment with (212)Pb-TCMC-trastuzumab and compared with groups treated with paclitaxel alone, (212)Pb-TCMC-HuIgG, (212)Pb-TCMC-trastuzumab and (212)Pb-TCMC-HuIgG after paclitaxel pre-treatment.
RESULTS: (212)Pb-TCMC-trastuzumab with paclitaxel given 24 h earlier induced increased mitotic catastrophe and apoptosis. The combined modality of paclitaxel and (212)Pb-TCMC-trastuzumab markedly reduced DNA content in the S-phase of the cell cycle with a concomitant increase observed in the G2/M-phase. This treatment regimen also diminished phosphorylation of histone H3, accompanied by an increase in multi-micronuclei, or mitotic catastrophe in nuclear profiles and positively stained γH2AX foci. The data suggests, possible effects on the mitotic spindle checkpoint by the paclitaxel and (212)Pb-TCMC-trastuzumab treatment. Consistent with this hypothesis, (212)Pb-TCMC-trastuzumab treatment in response to paclitaxel reduced expression and phosphorylation of BubR1, which is likely attributable to disruption of a functional Aurora B, leading to impairment of the mitotic spindle checkpoint. In addition, the reduction of BubR1 expression may be mediated by the association of a repressive transcription factor, E2F4, on the promoter region of BubR1 gene.
CONCLUSION: These findings suggest that the sensitisation to therapy of (212)Pb-TCMC-trastuzumab by paclitaxel may be associated with perturbation of the mitotic spindle checkpoint, leading to increased mitotic catastrophe and cell death.

Dodurga Y, Oymak Y, Gündüz C, et al.
Leukemogenesis as a new approach to investigate the correlation between up regulated gene 4/upregulator of cell proliferation (URG4/URGCP) and signal transduction genes in leukemia.
Mol Biol Rep. 2013; 40(4):3043-8 [PubMed] Related Publications
The aim of the study is to the determine the profiles of cell cycle genes and a new candidate oncogene of URG4/URGCP which play role in leukemia, establishing the association between the early prognosis of cancer and the quantitation of genetic changes, and bringing a molecular approach to definite diagnosis. In this study, 36 newly diagnosed patients' with ALL-AML in the range of 0-18 years and six control group patients' bone marrow samples were included. Total RNA was isolated from samples and then complementary DNA synthesis was performed. The obtained cDNAs have been installed 96 well plates after prepared appropriate mixtures and assessed with LightCycler(®) 480 Real-Time PCR quantitatively. CHEK1, URG4/URGCP, CCNG1, CCNC, CDC16, KRAS, CDKN2D genes in the T-ALL group; CCND2, ATM, CDK8, CHEK1, TP53, CHEK2, CCNG2, CDK4, CDKN2A, E2F4, CCNC, KRAS genes in the precursor B-ALL group and CCND2, CDK6 genes in the AML group have shown significant increase in mRNA expression level. In the featured role of acute leukemia the regulating signaling pathways of leukemogenesis partially defined, although identification of new genetic markers in acute leukemia subgroups, will allow the development of early diagnostic and new treatment protocols.

Zhu XL, Ai ZH, Wang J, et al.
Weighted gene co-expression network analysis in identification of endometrial cancer prognosis markers.
Asian Pac J Cancer Prev. 2012; 13(9):4607-11 [PubMed] Related Publications
OBJECTIVE: Endometrial cancer (EC) is the most common gynecologic malignancy. Identification of potential biomarkers of EC would be helpful for the detection and monitoring of malignancy, improving clinical outcomes.
METHODS: The Weighted Gene Co-expression Network Analysis method was used to identify prognostic markers for EC in this study. Moreover, underlying molecular mechanisms were characterized by KEGG pathway enrichment and transcriptional regulation analyses.
RESULTS: Seven gene co-expression modules were obtained, but only the turquoise module was positively related with EC stage. Among the genes in the turquoise module, COL5A2 (collagen, type V, alpha 2) could be regulated by PBX (pre-B-cell leukemia homeobox 1)1/2 and HOXB1(homeobox B1) transcription factors to be involved in the focal adhesion pathway; CENP-E (centromere protein E, 312kDa) by E2F4 (E2F transcription factor 4, p107/p130-binding); MYCN (v-myc myelocytomatosis viral related oncogene, neuroblastoma derived [avian]) by PAX5 (paired box 5); and BCL-2 (B-cell CLL/ lymphoma 2) and IGFBP-6 (insulin-like growth factor binding protein 6) by GLI1. They were predicted to be associated with EC progression via Hedgehog signaling and other cancer related-pathways.
CONCLUSIONS: These data on transcriptional regulation may provide a better understanding of molecular mechanisms and clues to potential therapeutic targets in the treatment of EC.

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