Gene Summary

Gene:CEBPD; CCAAT/enhancer binding protein delta
Aliases: CELF, CRP3, C/EBP-delta, NF-IL6-beta
Summary:The protein encoded by this intronless gene is a bZIP transcription factor which can bind as a homodimer to certain DNA regulatory regions. It can also form heterodimers with the related protein CEBP-alpha. The encoded protein is important in the regulation of genes involved in immune and inflammatory responses, and may be involved in the regulation of genes associated with activation and/or differentiation of macrophages. The cytogenetic location of this locus has been reported as both 8p11 and 8q11. [provided by RefSeq, Sep 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:CCAAT/enhancer-binding protein delta
Source:NCBIAccessed: 15 March, 2017


What does this gene/protein do?
Show (5)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 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.

  • Virus Replication
  • Western Blotting
  • Transcription Factors
  • CCAAT-Enhancer-Binding Proteins
  • Liver Cancer
  • Gene Regulatory Networks
  • Binding Sites
  • Signal Transduction
  • Up-Regulation
  • Cell Differentiation
  • DNA-Binding Proteins
  • Trans-Activators
  • DNA Sequence Analysis
  • Acute Myeloid Leukaemia
  • Molecular Sequence Data
  • Messenger RNA
  • Transcription
  • Gene Expression Profiling
  • Nuclear Proteins
  • User-Computer Interface
  • CCAAT-Enhancer-Binding Protein-beta
  • Chromosome 8
  • Hepatocellular Carcinoma
  • Cell Proliferation
  • Biomarkers, Tumor
  • Prostate Cancer
  • Base Sequence
  • Mutation
  • Apoptosis
  • Gene Expression Regulation
  • Young Adult
  • Cancer Gene Expression Regulation
  • Recurrence
  • Breast Cancer
  • Promoter Regions
  • Oligonucleotide Array Sequence Analysis
  • Interleukin-6
  • CCAAT-Enhancer-Binding Protein-delta
  • FISH
  • Urinary System Cancers
  • Neoplastic Cell Transformation
Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: CEBPD (cancer-related)

Xia L, Sun C, Li Q, et al.
CELF1 is Up-Regulated in Glioma and Promotes Glioma Cell Proliferation by Suppression of CDKN1B.
Int J Biol Sci. 2015; 11(11):1314-24 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: As a member of the CELF family, CELF1 (CUG-binding protein 1, CUGBP1) is involved in cardiac and embryonic development, skeletal muscle differentiation and mammary epithelial cell proliferation. CELF1 is also observed in many kinds of cancer and may play a great role in tumorigenesis and deterioration. However, the expression and mechanism of its function in human glioma remain unclear.
METHODS: We examined CELF1 expression in 62 glioma patients by immunohistochemistry and Western blot. The association between the expression of CELF1 protein and clinicopathological characteristics was analysed using SPSS 17.0. Survival analyses were performed using the Kaplan-Meier method. Small-interfering RNA was utilised to specifically knockdown CELF1 mRNA in U87 and U251 cells. Cell proliferation, cell cycle and cell apoptosis were tested by Cell Counting Kit-8 and flow cytometry. The expression of cell cycle-related gene CDKN1B was investigated by Western blot. The interactions between CELF1 and CDKN1B were detected with immune co-precipitation. Subcutaneous tumour models were used to study the effect of CELF1 on the growth of glioma cells in vivo.
RESULTS: Our results showed that CELF1 protein was frequently up-regulated in human glioma tissues. The expression level of this protein was positively correlated with glioma World Health Organisation grade and inversely correlated with patient survival (P < 0.05). Knockdown of CELF1 inhibited the glioma cell cycle process and proliferation potential, possibly by down-regulating its target, CDKN1B protein.
CONCLUSIONS: Results indicated that CELF1 may be a novel independent prognostic predictor of survival for glioma patients. It may promote glioma cell proliferation and cell cycle process during glioma carcinogenesis.

Li CF, Tsai HH, Ko CY, et al.
HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells.
Mol Cancer Ther. 2015; 14(11):2623-33 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) can arise from chronic inflammation due to viral infection, organ damage, drug toxicity, or alcohol abuse. Moreover, gene desensitization via aberrant CpG island methylation is a frequent epigenetic defect in HCC. However, the details of how inflammation is linked with epigenetic-mediated desensitization of tumor suppressor genes remains less investigated. In this study, we found that loss of CEBPD enhances the growth of liver cancer cells and is associated with the occurrence of liver cancers, as determined by the assessment of clinical specimens and in vivo animal models. Moreover, E2F1-regulated epigenetic axis attenuated CEBPD expression in liver cancer cells. CEBPD is responsive to the hydroxymethyldibenzoylmethane (HMDB)-induced p38/CREB pathway and plays an important role in the HMDB-induced apoptosis of cancer cells. Regarding depression of epigenetic effects to enhance HMDB-induced CEBPD expression, the combination of HMDB and 5-Aza-2'-deoxycytidine (5-AzadC) could enhance the death of liver cancer cells and reduce the tumor formation of Huh7 xenograft mice. In conclusion, these results suggest that CEBPD could be a useful diagnostic marker and therapeutic target in HCC. The results also reveal the therapeutic potential for low-dose 5-AzadC to enhance the HMDB-induced death of HCC cells.

Guo YM, Sun MX, Li J, et al.
Association of CELF2 polymorphism and the prognosis of nasopharyngeal carcinoma in southern Chinese population.
Oncotarget. 2015; 6(29):27176-86 [PubMed] Free Access to Full Article Related Publications
Nasopharyngeal carcinoma (NPC) is a malignancy with high metastatic potential and loco-regional recurrence. The overall survival of NPC has been limited from further improvement partly due to the lack of effective biomarker for accurate prognosis prediction and precise treatments. Here, in light of the implication of CELF gene family in cancer prognosis, we selected 112 tagging single nucleotide polymorphisms (SNPs) located in six members of the family and tested their associations with the clinical outcomes in a discovery cohort of 717 NPC patients. Survival analyses under multivariate cox proportional hazards model and Kaplan-Meier curve revealed five promising SNPs, which were further validated in another independent sample of 1,520 cases. Combined analysis revealed that SNP rs3740194 in CELF2 was significantly associated with the decreased risk of death with a Hazard ratio (HR) of 0.69 (95% confidence interval [CI] = 0.58-0.82, codominant model). Moreover, rs3740194 also showed a significant association with superior metastasis-free survival (HR = 0.69, 95% CI = 0.57-0.83, codominant model). Taken together, our findings suggested that genetic variant of rs3740194 in CELF2 gene might be a valuable predictor for NPC prognosis, and potentially useful in the personalized treatment of NPC.

Wang YH, Wu WJ, Wang WJ, et al.
CEBPD amplification and overexpression in urothelial carcinoma: a driver of tumor metastasis indicating adverse prognosis.
Oncotarget. 2015; 6(31):31069-84 [PubMed] Free Access to Full Article Related Publications
The molecular aberrations responsible for the progression of urothelial carcinoma (UC) remain largely obscure. To search candidate driver oncogenes in UC, we performed array-based genomic hybridization (aCGH) on 40 UBUC samples. Amplification of 8q11.21 was preferentially identified in patients who developed disease-specific death (53.8%) and distal metastasis (50.0%) but was barely detected in non-eventful cases (3.7% and 0%, respectively). In order to quantify the expression of candidate genes harbored in 8q11.21, laser-capture microdissection coupled with RT-PCR was performed on 32 of the 40 cases submitted to aCGH. With this, we identified CEBPD mRNA expression as most significantly associated with gains of 8q11.21, suggesting amplification-driven expression. By performing CEBPD-specific FISH and immunohistochemistry on 295 UBUCs, we confirmed CEBPD amplification (21.3%) and overexpression (29.8%) were strongly related to each other (p<0.001). Moreover, both were associated with adverse clinicopathologic features and worse outcomes. Furthermore, the clinical significance of CEBPD expression was also confirmed in an independent cohort comprised of 340 UCs from the upper urinary tract. Interestingly, CEBPD knockdown suppressed cell proliferation, migration and, most significantly, cell invasion ability in UC cells. The latter phenotype is attributed to downregulation of MMP2 as identified by RT2 Profiler PCR array. Moreover, expression of CEBPD significantly enhanced MMP2 expression and transcriptional activation by directly binding to its promoter region, as confirmed by promoter reporter assay and chromatin immunoprecipitation assay. Conclusively, CEBPD amplification is a mechanism driving increased mRNA and protein expression that confers aggressiveness in UC through MMP2-mediated cell invasiveness.

Jang JH, Min KJ, Kim S, et al.
RU486 Induces Pro-Apoptotic Endoplasmic Reticulum Stress Through the Induction of CHOP Expression by Enhancing C/EBPδ Expression in Human Renal Carcinoma Caki Cells.
J Cell Biochem. 2016; 117(2):361-9 [PubMed] Related Publications
RU486 (Mifepristone) is known as an antagonist of the progesterone receptor and glucocorticoid receptor. Here, we investigated the mechanism underlying anti-tumor activity of RU486 in renal carcinoma Caki cells. Treatment of Caki cells with RU486 was found to induce several signature ER stress markers; including ER stress-specific XBP1 splicing, and the up-regulation of glucose-regulated protein (GRP)-78 and CCAAT/enhancer-binding protein homologous protein (CHOP) expression. RU486-induced expression of CHOP involves the putative C/EBPδ site within the CHOP promoter region. Using a combination of C/EBPδ cDNA transfection, the luciferase assay with a mutated C/EBPδ binding site and siRNA-mediated C/EBPδ knockdown, we found that the C/EBPδ site is required for RU486-mediated activation of the CHOP promoter. In addition, RU486-induced CHOP expression is down-regulated by inhibition of the p38 MAPK and JNK signaling pathways at the post-translational levels. RU486 dose-dependently induced apoptotic cell death in renal carcinoma cells. Suppression of CHOP expression by CHOP siRNA attenuated RU486-induced apoptosis. Taken together, RU486 induces pro-apoptotic ER stress through the induction of CHOP expression.

Fan B, Jiao BH, Fan FS, et al.
Downregulation of miR-95-3p inhibits proliferation, and invasion promoting apoptosis of glioma cells by targeting CELF2.
Int J Oncol. 2015; 47(3):1025-33 [PubMed] Related Publications
Gliomas are the most common and aggressive types of tumors in human brain, of which the prognosis remains dismal because of their biological behavior. The involvement of miRNAs in tumorigenesis of various kinds of cancers drives us to explore new miRNAs related to gliomas. We measured expression level of miR‑95‑3p by qRT-PCR in human glioma and non-neoplasm brain tissues and found that higher level of miR‑95‑3p in glioma tissues of higher grade. Biological functions of miR‑95‑3p on glioma cells were investigated by MTT assay, flow cytometry and transwell assay. We discovered the cell lines transfected with miR‑95‑3p ASO (antisense oligonucleotide) had retarded proliferation and invasion but enhanced apoptosis ability. We searched on-line tool Targetscan and selected CELF (CUGBP- and ETR-3-like family 2) as a putative target. Luciferase reporter was employed to confirm the binding sites in 3'UTR region of CELF2 for miR‑95‑3p. The correlation between expression of CELF2 and miR‑95‑3p was determined by western blotting and qRT-PCR both in cell lines and human samples. Results showed CELF2 was a direct target of miR‑95‑3p and expression levels of CELF2 and miR‑95‑3p were negatively correlated. Finally, CELF2 largely abrogated the effects of miR‑95‑3p on proliferation, invasion and apoptosis of glioma cells in rescue experiments, which verified the role of CELF2 in miR‑95‑3p regulating glioma biological behavior. In conclusion, our data suggest the expression level of miR‑95‑3p is positively related to glioma grade and downregulation of miR‑95‑3p affects proliferation, invasion and apoptosis of glioma cells by targeting CELF2. We identified miR‑95‑3p as a putative therapeutic target and CELF2 as a potential tumor suppressor.

Chi JY, Hsiao YW, Li CF, et al.
Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drug-resistant cancers.
Oncotarget. 2015; 6(27):23987-4001 [PubMed] Free Access to Full Article Related Publications
The tumor microenvironment has been suggested to participate in tumorigenesis, but the nature of the communication between cancer cells and the microenvironment, especially in response to anticancer drugs, remains obscure. We determined that activation of the CCAAT/enhancer binding protein delta (CEBPD) response to Cisplatin and 5-Fluorouracil in cancer-associated macrophages and fibroblasts contributed to the metastasis, invasion, acquired chemoresistance and stemness of cancer cells by in vitro and in vivo assays. Specifically, reporter and in vivo DNA binding assays were used to determine that Pentraxin 3 (PTX3) is a CEBPD responsive gene and serves a protumor role upon anticancer drug treatment. Finally, a PTX3 peptide inhibitor RI37 was developed and assessed the antitumor effects by in vivo assays. RI37 could function as a promising inhibitor for preventing cancer progression and the metastasis, invasion and progression of drug-resistant cancers. The identification of PTX3 provided a new insight in the interaction between host and tumor and the RI37 peptide showed a great opportunity to largely reduce the risk of invasion and metastasis of cancer and drug-resistant cancers.

Lv M, Wang L
Comprehensive analysis of genes, pathways, and TFs in nonsmoking Taiwan females with lung cancer.
Exp Lung Res. 2015; 41(2):74-83 [PubMed] Related Publications
PURPOSE: The aim of this study was to investigate the molecular mechanism of lung cancer among nonsmoking Taiwan females.
MATERIALS AND METHODS: By using the GSE19804 microarray data accessible from Gene Expression Omnibus (GEO) database, we identified differentially expressed genes (DEGs) between nonsmoking female lung cancer patients and healthy controls (!logFC! >1.5 and p-value < 0.05). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene ontology (GO) enrichment analysis was performed using Database for Annotation, Visualization and Integrated Discovery (DAVID). The Search Tool for the Retrieval of Interacting Genes (STRING) tool was utilized to build a protein-protein interaction (PPI) network, followed by the construction of a transcriptional regulatory network based on Transcription factor (TRANSFAC) database.
RESULTS: As a result, 320 DEGs were identified between nonsmoking female patients with lung cancer and healthy controls. Pathway enrichment analysis showed significantly enriched pathways such as extracellular matrix (ECM)-receptor interaction and peroxisome proliferator-activated receptor (PPAR) signaling pathway, both of which were enriched with genes COL11A1 (encoding collagen XI alpha-1 chain protein), COL1A1, cluster of differentiation 36(CD36). GO enrichment analysis found that DEGs were significantly related to chemotaxis, vasculature development and cell adhesion GO terms. IL-6 was the node of the PPI network. Critical transcription factors (TFs) including CCAAT/enhancer-binding protein delta (CEBPD) and Rel/NF-κB were also identified.
CONCLUSIONS: Our study revealed that ECM-receptor interaction, PPAR signaling pathways, and important biomolecules including COL11A1, COL1A1, CD36, IL-6, CEBPD, and Rel/NF-κB might be involved in lung cancer. This study might pave the way for the development and application of targeted therapeutics of lung cancer irrelevant to smoking.

Liu J, Li J, Li H, et al.
A comprehensive analysis of candidate genes and pathways in pancreatic cancer.
Tumour Biol. 2015; 36(3):1849-57 [PubMed] Related Publications
The study aimed to dissect the molecular mechanism of pancreatic cancer by a range of bioinformatics approaches. Three microarray datasets (GSE32676, GSE21654, and GSE14245) were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) with logarithm of fold change (|logFC|) >0.585 and p value <0.05 were identified between pancreatic cancer samples and normal controls. Transcription factors (TFs) were selected from the DEGs based on TRASFAC database. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed for the DEGs using The Database for Annotation, Visualization and Integrated Discovery (p value <0.05), followed by construction of protein-protein interaction (PPI) network using Search Tool for the Retrieval of Interacting Genes software. Latent pathway identification analysis was applied to analyze the DEGs-related pathways crosstalk and the pathways with high weight value were included in the pathway crosstalk network using Cytoscape. Sixty-five DEGs were screened out. CCAAT/enhancer-binding protein delta (CEBPD), FBJ osteosarcoma oncogene B (FOSB), Stratifin (SFN), Krüppel-like factor 5 (KLF5), Pentraxin 3 (PTX3), and nuclear receptor subfamily 4, group A, member 3 (NR4A3) were important TFs. Interleukin-6 (IL-6) was the hub node of the PPI network. DEGs were significantly enriched in NOD-like receptor signaling pathway which was primarily interacted with inflammation and immune related pathways (cytosolic DNA-sensing, hematopoietic cell lineage, intestinal immune network for IgA production and chemokine pathways). The study suggested CEBPD, FOSB, SFN, KLF5, PTX3, NR4A3, IL-6, and NOD-like receptor pathways were involved in pancreatic cancer.

Chen JC, Alvarez MJ, Talos F, et al.
Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks.
Cell. 2014; 159(2):402-14 [PubMed] Free Access to Full Article Related Publications
Identification of driver mutations in human diseases is often limited by cohort size and availability of appropriate statistical models. We propose a framework for the systematic discovery of genetic alterations that are causal determinants of disease, by prioritizing genes upstream of functional disease drivers, within regulatory networks inferred de novo from experimental data. We tested this framework by identifying the genetic determinants of the mesenchymal subtype of glioblastoma. Our analysis uncovered KLHL9 deletions as upstream activators of two previously established master regulators of the subtype, C/EBPβ and C/EBPδ. Rescue of KLHL9 expression induced proteasomal degradation of C/EBP proteins, abrogated the mesenchymal signature, and reduced tumor viability in vitro and in vivo. Deletions of KLHL9 were confirmed in > 50% of mesenchymal cases in an independent cohort, thus representing the most frequent genetic determinant of the subtype. The method generalized to study other human diseases, including breast cancer and Alzheimer's disease.

Wang L, Ye X, Liu Y, et al.
Aberrant regulation of FBW7 in cancer.
Oncotarget. 2014; 5(8):2000-15 [PubMed] Free Access to Full Article Related Publications
FBW7 (F-box and WD repeat domain-containing 7) or Fbxw7 is a tumor suppressor, which promotes the ubiquitination and subsequent degradation of numerous oncoproteins including Mcl-1, Cyclin E, Notch, c- Jun, and c-Myc. In turn, FBW7 is regulated by multiple upstream factors including p53, C/EBP-δ, EBP2, Pin1, Hes-5 and Numb4 as well as by microRNAs such as miR-223, miR-27a, miR-25, and miR-129-5p. Given that the Fbw7 tumor suppressor is frequently inactivated or deleted in various human cancers, targeting FBW7 regulators is a promising anti-cancer therapeutic strategy.

Musialik E, Bujko M, Kober P, et al.
Comparison of promoter DNA methylation and expression levels of genes encoding CCAAT/enhancer binding proteins in AML patients.
Leuk Res. 2014; 38(7):850-6 [PubMed] Related Publications
CCAAT/enhancer binding proteins (CEBPs) are transcription factors regulating myeloid differentiation. Disturbances of their expression may contribute to leukemogenesis. In this study we compared promoter methylation and expression levels of selected CEBP genes in a group of 78 AML patients, normal bone marrow and hematopoietic precursor cells. CEBPA, CEBPD and CEBPE promoter methylation levels were elevated in 37%, 35.5% and 56.7% of patients. No CEBPZ(DDIT3) methylation was observed. An inverse relationship between CEBPA and CEBPD DNA methylation and expression levels was observed. AML cytogenetic risk groups and patients with particular translocation are characterized by distinct methylation/expression profile of CEBPs encoding genes.

Chuang CH, Wang WJ, Li CF, et al.
The combination of the prodrugs perforin-CEBPD and perforin-granzyme B efficiently enhances the activation of caspase signaling and kills prostate cancer.
Cell Death Dis. 2014; 5:e1220 [PubMed] Free Access to Full Article Related Publications
The survival of prostate cancer (PrCa) patients is associated with the transition to hormone-independent tumor growth and metastasis. Clinically, the dysregulation of androgen action has been associated with the formation of PrCa and the outcome of androgen deprivation therapy in PrCa. CCAAT/enhancer binding protein delta (CEBPD) is a transcription factor that has been reported to act as an oncogene or tumor suppressor, depending on the extra- and intracellular environments following tumorigenesis. We found that androgen can activate CEBPD transcription by direct binding of the androgen receptor (AR) to the CEBPD promoter region. Increases of suppressor of zeste 12 (SUZ12) and enhancer of zeste homolog 2 (EZH2) attenuated the androgen-induced transcription of CEBPD. Importantly, the increases in E2F1, SUZ12 and EZH2 as well as the inactivation of CEBPD were associated with the clinicopathological variables and survival of PrCa patients. We revealed that caspase 8 (CASP8), an apoptotic initiator, is responsive to CEBPD induction. Reporter and in vivo DNA-binding assays revealed that CEBPD directly binds to and activates CASP8 reporter activity. A prodrug system was developed for therapeutic application in AR-independent or androgen-insensitive PrCa to avoid the epigenetic effects on the suppression of CEBPD expression. Our results showed that the combination of a perforin (PF)-CEBPD prodrug (which increases the level of procaspase-8) and a PF-granzyme B prodrug (which activates CASP8 and caspase 3 (CASP3)) showed an additive effect in triggering the apoptotic pathway and enhancing apoptosis in PrCa cells.

Balamurugan K, Sterneck E
The many faces of C/EBPδ and their relevance for inflammation and cancer.
Int J Biol Sci. 2013; 9(9):917-33 [PubMed] Free Access to Full Article Related Publications
The CCAAT/enhancer binding protein delta (CEBPD, C/EBPδ) is a transcription factor that modulates many biological processes including cell differentiation, motility, growth arrest, proliferation, and cell death. The diversity of C/EBPδ's functions depends in part on the cell type and cellular context and can have opposing outcomes. For example, C/EBPδ promotes inflammatory signaling, but it can also inhibit pro-inflammatory pathways, and in a mouse model of mammary tumorigenesis, C/EBPδ reduces tumor incidence but promotes tumor metastasis. This review highlights the multifaceted nature of C/EBPδ's functions, with an emphasis on pathways that are relevant for cancer and inflammation, and illustrates how C/EBPδ emerged from the shadow of its family members as a fascinating "jack of all trades." Our current knowledge on C/EBPδ indicates that, rather than being essential for a specific cellular process, C/EBPδ helps to interpret a variety of cues in a cell-type and context-dependent manner, to adjust cellular functions to specific situations. Therefore, insights into the roles and mechanisms of C/EBPδ signaling can lead to a better understanding of how the integration of different signaling pathways dictates normal and pathological cell functions and physiology.

Kandilci A, Surtel J, Janke L, et al.
Mapping of MN1 sequences necessary for myeloid transformation.
PLoS One. 2013; 8(4):e61706 [PubMed] Free Access to Full Article Related Publications
The MN1 oncogene is deregulated in human acute myeloid leukemia and its overexpression induces proliferation and represses myeloid differentiation of primitive human and mouse hematopoietic cells, leading to myeloid leukemia in mouse models. To delineate the sequences within MN1 necessary for MN1-induced leukemia, we tested the transforming capacity of in-frame deletion mutants, using retroviral transduction of mouse bone marrow. We found that integrity of the regions between amino acids 12 to 458 and 1119 to 1273 are required for MN1's in vivo transforming activity, generating myeloid leukemia with some mutants also producing T-cell lympho-leukemia and megakaryocytic leukemia. Although both full length MN1 and a mutant that lacks the residues between 12-228 (Δ12-228 mutant) repressed myeloid differentiation and increased myeloproliferative activity in vitro, the mutant lost its transforming activity in vivo. Both MN1 and Δ12-228 increased the frequency of common myeloid progentiors (CMP) in vitro and microarray comparisons of purified MN1-CMP and Δ12-228-CMP cells showed many differentially expressed genes including Hoxa9, Meis1, Myb, Runx2, Cebpa, Cebpb and Cebpd. This collection of immediate MN1-responsive candidate genes distinguishes the leukemic activity from the in vitro myeloproliferative capacity of this oncoprotein.

Brueckner LM, Hess EM, Schwab M, Savelyeva L
Instability at the FRA8I common fragile site disrupts the genomic integrity of the KIAA0146, CEBPD and PRKDC genes in colorectal cancer.
Cancer Lett. 2013; 336(1):85-95 [PubMed] Related Publications
Specific patterns of genomic aberrations have been associated with different types of malignancies. In colorectal cancer, losses of chromosome arm 8p and gains of chromosome arm 8q are among the most common chromosomal rearrangements, suggesting that the centromeric portion of chromosome 8 is particularly sensitive to breakage. Genomic alterations frequently occur in the early stages of tumorigenesis at specific genomic regions known as common fragile sites (cFSs). CFSs represent parts of the normal chromosome structure that are prone to breakage under replication stress. In this study, we identified the genomic location of FRA8I, spanning 530 kb at 8q11.21 and assessed the composition of the fragile DNA sequence. FRA8I encompasses KIAA0146, a large protein-coding gene with yet unknown function, as well as CEBPD and part of PRKDC, two genes encoding proteins involved in tumorigenesis in a variety of cancers. We show that FRA8I is unstable in lymphocytes and epithelial cells, displaying similar expression rates. We examined copy number alteration patterns within FRA8I in a panel of 25 colorectal cancer cell lines and surveyed publically available profiles of 56 additional colorectal cancer cell lines. Combining these data shows that focal recombination events disrupt the genomic integrity of KIAA0146 and neighboring cFS genes in 12.3% of colorectal cancer cell lines. Moreover, data analysis revealed evidence that KIAA0146 is a translocation partner of the immunoglobulin heavy chain gene in recurrent t(8;14)(q11;q32) translocations in a subset of patients with B-cell precursor acute lymphoblastic leukemia. Our data molecularly describe a region of enhanced chromosomal instability in the human genome and point to a role of the KIAA0146 gene in tumorigenesis.

Fleming VA, Geng C, Ladd AN, Lou H
Alternative splicing of the neurofibromatosis type 1 pre-mRNA is regulated by the muscleblind-like proteins and the CUG-BP and ELAV-like factors.
BMC Mol Biol. 2012; 13:35 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Alternative splicing is often subjected to complex regulatory control that involves many protein factors and cis-acting RNA sequence elements. One major challenge is to identify all of the protein players and define how they control alternative expression of a particular exon in a combinatorial manner. The Muscleblind-like (MBNL) and CUG-BP and ELAV-Like family (CELF) proteins are splicing regulatory proteins, which function as antagonists in the regulation of several alternative exons. Currently only a limited number of common targets of MBNL and CELF are known that are antagonistically regulated by these two groups of proteins.
RESULTS: Recently, we identified neurofibromatosis type 1 (NF1) exon 23a as a novel target of negative regulation by CELF proteins. Here we report that MBNL family members are positive regulators of this exon. Overexpression of MBNL proteins promote exon 23a inclusion in a low MBNL-expressing cell line, and simultaneous siRNA-mediated knockdown of MBNL1 and MBNL2 family members in a high MBNL-expressing cell line promotes exon 23a skipping. Importantly, these two groups of proteins antagonize each other in regulating inclusion of exon 23a. Furthermore, we analyzed the binding sites of these proteins in the intronic sequences upstream of exon 23a by UV cross-linking assays. We show that in vitro, in addition to the previously identified preferred binding sequence UGCUGU, the MBNL proteins need the neighboring sequences for optimal binding.
CONCLUSION: This study along with our previous work that demonstrated roles for Hu, CELF, and TIA-1 and TIAR proteins in the regulation of NF1 exon 23a establish that this exon is under tight, complex control.

Tong Y, Zheng Y, Zhou J, et al.
Genomic characterization of human and rat prolactinomas.
Endocrinology. 2012; 153(8):3679-91 [PubMed] Free Access to Full Article Related Publications
Although prolactinomas can be effectively treated with dopamine agonists, about 20% of patients develop dopamine resistance or tumor recurrence after surgery, indicating a need for better understanding of underlying disease mechanisms. Although estrogen-induced rat prolactinomas have been widely used to investigate the development of this tumor, the extent that the model recapitulates features of human prolactinomas is unclear. To prioritize candidate genes and gene sets regulating human and rat prolactinomas, microarray results derived from human prolactinomas and pituitaries of estrogen-treated ACI rats were integrated and analyzed. A total of 4545 differentially expressed pituitary genes were identified in estrogen-treated ACI rats [false discovery rate (FDR) < 0.01]. By comparing pituitary microarray results derived from estrogen-treated Brown Norway rats (a strain not sensitive to estrogen), 4073 genes were shown specific to estrogen-treated ACI rats. Human prolactinomas exhibited 1177 differentially expressed genes (FDR < 0.05). Combining microarray data derived from human prolactinoma and pituitaries of estrogen-treated ACI rat, 145 concordantly expressed genes, including E2F1, Myc, Igf1, and CEBPD, were identified. Gene set enrichment analysis revealed that 278 curated pathways and 59 gene sets of transcription factors were enriched (FDR < 25%) in estrogen-treated ACI rats, suggesting a critical role for Myc, E2F1, CEBPD, and Sp1 in this rat prolactinoma. Similarly increased Myc, E2F1, and Sp1 expression was validated using real-time PCR and Western blot in estrogen-treated Fischer rat pituitary glands. In summary, characterization of individual genes and gene sets in human and in estrogen-induced rat prolactinomas validates the model and provides insights into genomic changes associated with this commonly encountered pituitary tumor.

Cooper LA, Gutman DA, Chisolm C, et al.
The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma.
Am J Pathol. 2012; 180(5):2108-19 [PubMed] Free Access to Full Article Related Publications
The Cancer Genome Atlas (TCGA) project has generated gene expression data that divides glioblastoma (GBM) into four transcriptional classes: proneural, neural, classical, and mesenchymal. Because transcriptional class is only partially explained by underlying genomic alterations, we hypothesize that the tumor microenvironment may also have an impact. In this study, we focused on necrosis and angiogenesis because their presence is both prognostically and biologically significant. These features were quantified in digitized histological images of TCGA GBM frozen section slides that were immediately adjacent to samples used for molecular analysis. Correlating these features with transcriptional data, we found that the mesenchymal transcriptional class was significantly enriched with GBM samples that contained a high degree of necrosis. Furthermore, among 2422 genes that correlated with the degree of necrosis in GBMs, transcription factors known to drive the mesenchymal expression class were most closely related, including C/EBP-β, C/EBP-δ, STAT3, FOSL2, bHLHE40, and RUNX1. Non-mesenchymal GBMs in the TCGA data set were found to become more transcriptionally similar to the mesenchymal class with increasing levels of necrosis. In addition, high expression levels of the master mesenchymal factors C/EBP-β, C/EBP-δ, and STAT3 were associated with a poor prognosis. Strong, specific expression of C/EBP-β and C/EBP-δ by hypoxic, perinecrotic cells in GBM likely account for their tight association with necrosis and may be related to their poor prognosis.

Marrero D, Peralta R, Valdivia A, et al.
The neurofibromin 1 type I isoform predominance characterises female population affected by sporadic breast cancer: preliminary data.
J Clin Pathol. 2012; 65(5):419-23 [PubMed] Related Publications
AIMS: Neurofibromin 1 (NF1) as a tumour suppressor gene can give rise to several transcripts by an alternative splicing event, generated at least for CELF cofactors. At present, the NF1 isoforms and CELF splicing transcripts in sporadic breast cancer are unknown. The aim of the authors was to detect NF1 gene expression, the NF1 isoform ratio and the CELF transcripts present in sporadic breast cancer.
METHODS: Neurofibromin and RAS expression were analysed on tissue microarrays containing sporadic breast cancer (n=22), benign lesions (n=18, including six fibroadenomas, six fibrocystic changes and six ductal hyperplasias) and normal breast tissue (n=6) by immunohistochemistry assay. NF1 and CELF 3-6 RNA expression was performed by end point reverse transcription-PCR in the breast samples.
RESULTS: NF1 and RAS expression in breast tissues showed no differential expression by immunohistochemistry results. Interestingly, the authors observed a shift transition in the isoform transcripts, from type II in normal breast tissue to type I isoform in breast carcinomas. CELF cofactor expression failed to be related with the shift transition of NF1 in breast tissues.
CONCLUSIONS: These data suggest that there is a tendency for an NF1 expression shift transition from type II to type I isoform, which could comprise a significant event in the development and progression of sporadic breast cancer. This shift transition may not be related with CELF cofactors.

Moore F, Santin I, Nogueira TC, et al.
The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells.
PLoS One. 2012; 7(2):e31062 [PubMed] Free Access to Full Article Related Publications
In the course of Type 1 diabetes pro-inflammatory cytokines (e.g., IL-1β, IFN-γ and TNF-α) produced by islet-infiltrating immune cells modify expression of key gene networks in β-cells, leading to local inflammation and β-cell apoptosis. Most known cytokine-induced transcription factors have pro-apoptotic effects, and little is known regarding "protective" transcription factors. To this end, we presently evaluated the role of the transcription factor CCAAT/enhancer binding protein delta (C/EBPδ) on β-cell apoptosis and production of inflammatory mediators in the rat insulinoma INS-1E cells, in purified primary rat β-cells and in human islets. C/EBPδ is expressed and up-regulated in response to the cytokines IL-1β and IFN-γ in rat β-cells and human islets. Small interfering RNA-mediated C/EBPδ silencing exacerbated IL-1β+IFN-γ-induced caspase 9 and 3 cleavage and apoptosis in these cells. C/EBPδ deficiency increased the up-regulation of the transcription factor CHOP in response to cytokines, enhancing expression of the pro-apoptotic Bcl-2 family member BIM. Interfering with C/EBPδ and CHOP or C/EBPδ and BIM in double knockdown approaches abrogated the exacerbating effects of C/EBPδ deficiency on cytokine-induced β-cell apoptosis, while C/EBPδ overexpression inhibited BIM expression and partially protected β-cells against IL-1β+IFN-γ-induced apoptosis. Furthermore, C/EBPδ silencing boosted cytokine-induced production of the chemokines CXCL1, 9, 10 and CCL20 in β-cells by hampering IRF-1 up-regulation and increasing STAT1 activation in response to cytokines. These observations identify a novel function of C/EBPδ as a modulatory transcription factor that inhibits the pro-apoptotic and pro-inflammatory gene networks activated by cytokines in pancreatic β-cells.

Barron VA, Lou H
Alternative splicing of the neurofibromatosis type I pre-mRNA.
Biosci Rep. 2012; 32(2):131-8 [PubMed] Free Access to Full Article Related Publications
NF1 (neurofibromatosis type I) is a common genetic disease that affects one in 3500 individuals. The disease is completely penetrant but shows variable phenotypic expression in patients. NF1 is a large gene, and its pre-mRNA undergoes alternative splicing. The NF1 protein, neurofibromin, is involved in diverse signalling cascades. One of the best characterized functions of NF1 is its function as a Ras-GAP (GTPase-activating protein). NF1 exon 23a is an alternative exon that lies within the GAP-related domain of neurofibromin. This exon is predominantly included in most tissues, and it is skipped in CNS (central nervous system) neurons. The isoform in which exon 23a is skipped has 10 times higher Ras-GAP activity than the isoform in which exon 23a is included. Exon 23a inclusion is tightly regulated by at least three different families of RNA-binding proteins: CELF {CUG-BP (cytosine-uridine-guanine-binding protein) and ETR-3 [ELAV (embryonic lethal abnormal vision)-type RNA-binding protein]-like factor}, Hu and TIA-1 (T-cell intracellular antigen 1)/TIAR (T-cell intracellular antigen 1-related protein). The CELF and Hu proteins promote exon 23a skipping, while the TIA-1/TIAR proteins promote its inclusion. The widespread clinical variability that is observed among NF1 patients cannot be explained by NF1 mutations alone and it is believed that modifier genes may have a role in the variability. We suggest that the regulation of alternative splicing may act as a modifier to contribute to the variable expression in NF1 patients.

Sarkar TR, Sharan S, Wang J, et al.
Identification of a Src tyrosine kinase/SIAH2 E3 ubiquitin ligase pathway that regulates C/EBPδ expression and contributes to transformation of breast tumor cells.
Mol Cell Biol. 2012; 32(2):320-32 [PubMed] Free Access to Full Article Related Publications
The transcription factor CCAAT/enhancer-binding protein delta (C/EBPδ, CEBPD) is a tumor suppressor that is downregulated during breast cancer progression but may also promote metastasis. Here, we have investigated the mechanism(s) regulating C/EBPδ expression and its role in human breast cancer cells. We describe a novel pathway by which the tyrosine kinase Src downregulates C/EBPδ through the SIAH2 E3 ubiquitin ligase. Src phosphorylates SIAH2 in vitro and leads to tyrosine phosphorylation and activation of SIAH2 in breast tumor cell lines. SIAH2 interacts with C/EBPδ, but not C/EBPβ, and promotes its polyubiquitination and proteasomal degradation. Src/SIAH2-mediated inhibition of C/EBPδ expression supports elevated cyclin D1 levels, phosphorylation of retinoblastoma protein (Rb), motility, invasive properties, and survival of transformed cells. Pharmacological inhibition of Src family kinases by SKI-606 (bosutinib) induces C/EBPδ expression in an SIAH2-dependent manner, which is necessary for "therapeutic" responses to SKI-606 in vitro. Ectopic expression of degradation-resistant mutants of C/EBPδ, which do not interact with SIAH2 and/or cannot be polyubiquitinated, prevents full transformation of MCF-10A cells by activated Src (Src truncated at amino acid 531 [Src-531]) in vitro. These data reveal that C/EBPδ expression can be regulated at the protein level by oncogenic Src kinase signals through SIAH2, thus contributing to breast epithelial cell transformation.

Shapiro IM, Cheng AW, Flytzanis NC, et al.
An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype.
PLoS Genet. 2011; 7(8):e1002218 [PubMed] Free Access to Full Article Related Publications
Epithelial-mesenchymal transition (EMT), a mechanism important for embryonic development, plays a critical role during malignant transformation. While much is known about transcriptional regulation of EMT, alternative splicing of several genes has also been correlated with EMT progression, but the extent of splicing changes and their contributions to the morphological conversion accompanying EMT have not been investigated comprehensively. Using an established cell culture model and RNA-Seq analyses, we determined an alternative splicing signature for EMT. Genes encoding key drivers of EMT-dependent changes in cell phenotype, such as actin cytoskeleton remodeling, regulation of cell-cell junction formation, and regulation of cell migration, were enriched among EMT-associated alternatively splicing events. Our analysis suggested that most EMT-associated alternative splicing events are regulated by one or more members of the RBFOX, MBNL, CELF, hnRNP, or ESRP classes of splicing factors. The EMT alternative splicing signature was confirmed in human breast cancer cell lines, which could be classified into basal and luminal subtypes based exclusively on their EMT-associated splicing pattern. Expression of EMT-associated alternative mRNA transcripts was also observed in primary breast cancer samples, indicating that EMT-dependent splicing changes occur commonly in human tumors. The functional significance of EMT-associated alternative splicing was tested by expression of the epithelial-specific splicing factor ESRP1 or by depletion of RBFOX2 in mesenchymal cells, both of which elicited significant changes in cell morphology and motility towards an epithelial phenotype, suggesting that splicing regulation alone can drive critical aspects of EMT-associated phenotypic changes. The molecular description obtained here may aid in the development of new diagnostic and prognostic markers for analysis of breast cancer progression.

Min Y, Ghose S, Boelte K, et al.
C/EBP-δ regulates VEGF-C autocrine signaling in lymphangiogenesis and metastasis of lung cancer through HIF-1α.
Oncogene. 2011; 30(49):4901-9 [PubMed] Free Access to Full Article Related Publications
CCAAT/enhancer-binding protein-δ (C/EBP-δ), a transcription factor, is elevated in carcinoma compared with that in normal tissue. This study reports a novel function of C/EBP-δ in lymphangiogenesis and tumor metastasis. Genetic deletion of C/EBP-δ in mice resulted in a significant reduction of lymphangiogenesis and pulmonary metastases, with a dramatic reduction of vascular endothelial growth factor-C (VEGF-C) and its cognate receptor VEGF receptor-3 (VEGFR3) in lymphatic endothelial cells (LECs). By contrast, no difference of VEGF-C in tumor tissues and bone marrow was observed between null and wild-type mice. Consistently, forced expression of C/EBP-δ increased VEGF-C and VEGFR3 expression in cultured LECs. These findings suggest a specific and important role of C/EBP-δ in the regulation of VEGFR3 signaling in LECs. Furthermore, expression of C/EBP-δ in cultured LECs significantly increased cell motility, and knockdown of C/EBP-δ inhibited cell motility and lymphatic vascular network formation in vitro. Forced expression of VEGF-C, but not recombinant VEGF-C, rescued the knockdown of C/EBP-δ-induced cell apoptosis, indicative of autonomous VEGF-C autocrine signaling essential for LEC survival. Moreover, hypoxia induces C/EBP-δ expression and C/EBP-δ regulates HIF-1α expression. Blocking HIF-1α activity totally blocked CEBP-δ-induced VEGF-C and VEGFR3 expression in LECs. Together, these findings uncover a new function of CEBP-δ in lymphangiogenesis through regulation of VEGFR3 signaling in LECs.

Subramaniam D, Ramalingam S, Linehan DC, et al.
RNA binding protein CUGBP2/CELF2 mediates curcumin-induced mitotic catastrophe of pancreatic cancer cells.
PLoS One. 2011; 6(2):e16958 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Curcumin inhibits the growth of pancreatic cancer tumor xenografts in nude mice; however, the mechanism of action is not well understood. It is becoming increasingly clear that RNA binding proteins regulate posttranscriptional gene expression and play a critical role in RNA stability and translation. Here, we have determined that curcumin modulates the expression of RNA binding protein CUGBP2 to inhibit pancreatic cancer growth.
METHODOLOGY/PRINCIPAL FINDINGS: In this study, we show that curcumin treated tumor xenografts have a significant reduction in tumor volume and angiogenesis. Curcumin inhibited the proliferation, while inducing G2-M arrest and apoptosis resulting in mitotic catastrophe of various pancreatic cancer cells. This was further confirmed by increased phosphorylation of checkpoint kinase 2 (Chk2) protein coupled with higher levels of nuclear cyclin B1 and Cdc-2. Curcumin increased the expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) mRNA, but protein levels were lower. Furthermore, curcumin increased the expression of RNA binding proteins CUGBP2/CELF2 and TIA-1. CUGBP2 binding to COX-2 and VEGF mRNA was also enhanced, thereby increasing mRNA stability, the half-life changing from 30 min to 8 h. On the other hand, silencer-mediated knockdown of CUGBP2 partially restored the expression of COX-2 and VEGF even with curcumin treatment. COX-2 and VEGF mRNA levels were reduced to control levels, while proteins levels were higher.
CONCLUSION/SIGNIFICANCE: Curcumin inhibits pancreatic tumor growth through mitotic catastrophe by increasing the expression of RNA binding protein CUGBP2, thereby inhibiting the translation of COX-2 and VEGF mRNA. These data suggest that translation inhibition is a novel mechanism of action for curcumin during the therapeutic intervention of pancreatic cancers.

Pan YC, Li CF, Ko CY, et al.
CEBPD reverses RB/E2F1-mediated gene repression and participates in HMDB-induced apoptosis of cancer cells.
Clin Cancer Res. 2010; 16(23):5770-80 [PubMed] Related Publications
PURPOSE: Recent evidence indicates that a tumor suppressor gene CEBPD (CCAAT/enhancer-binding protein delta) is downregulated in many cancers including cervical cancer, which provides a therapeutic potential associated with its reactivation. However, little is known for CEBPD activators and the effect of reactivation of CEBPD transcription upon anticancer drug treatment. In this study, we identified a novel CEBPD activator, 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione (HMDB). The purpose of this study is to characterize the mechanism of HMDB-induced CEBPD activation and its potential effect in cancer therapy.
EXPERIMENTAL DESIGN: Methylation-specific PCR assay, reporter assay, and chromatin immunoprecipitation (ChIP) assay were performed to dissect the signaling pathway of HMDB-induced CEBPD transcription. Furthermore, a consequence of HMDB-induced CEBPD expression was linked with E2F1 and retinoblastoma (RB), which discloses the scenario of CEBPD, E2F1, and RB bindings and transcriptional regulation on the promoters of proapoptotic genes, PPARG2 and GADD153. Finally, the anticancer effect of HMDB was examined in xenograft mice.
RESULTS: We demonstrate that CEBPD plays an essential role in HMDB-mediated apoptosis of cancer cells. HMDB up-regulates CEBPD transcription through the p38/CREB pathway, thus leading to transcriptional activation of PPARG2 and GADD153. Furthermore, increased level of CEBPD attenuates E2F1-induced cancer cell proliferation and partially rescues RB/E2F1-mediated repression of PPARG2 and GADD153 transcription. Moreover, HMDB treatment attenuates the growth of A431 xenografts in severe combined immunodeficient mice mice.
CONCLUSIONS: These results clearly demonstrate that HMDB kills cancer cells through activation of CEBPD pathways and suggest that HMDB can serve as a superior chemotherapeutic agent with limited potential for adverse side effects.

Hour TC, Lai YL, Kuan CI, et al.
Transcriptional up-regulation of SOD1 by CEBPD: a potential target for cisplatin resistant human urothelial carcinoma cells.
Biochem Pharmacol. 2010; 80(3):325-34 [PubMed] Free Access to Full Article Related Publications
Bladder cancer is the fourth most common type of cancer in men (ninth in women) in the United States. Cisplatin is an effective agent against the most common subtype, urothelial carcinoma. However, the development of chemotherapy resistance is a severe clinical problem for the successful treatment of this and other cancers. A better understanding of the cellular and molecular events in response to cisplatin treatment and the development of resistance are critical to improve the therapeutic options for patients. Here, we report that expression of the CCAAT/enhancer binding protein delta (CEBPD, C/EBPdelta, NF-IL6beta) is induced by cisplatin in the human bladder urothelial carcinoma NTUB1 cell line and is specifically elevated in a cisplatin resistant subline. Expression of CEBPD reduced cisplatin-induced reactive oxygen species (ROS) and apoptosis in NTUB1 cells by inducing the expression of Cu/Zn-superoxide dismutase (SOD1) via direct promoter transactivation. Several reports have implicated CEBPD as a tumor suppressor gene. This study reveals a novel role for CEBPD in conferring drug resistance, suggesting that it can also be pro-oncogenic. Furthermore, our data suggest that SOD inhibitors, which are already used as anti-angiogenic agents, may be suitable for combinatorial chemotherapy to prevent or treat cisplatin resistance in bladder and possibly other cancers.

Karlsen JR, Borregaard N, Cowland JB
Induction of neutrophil gelatinase-associated lipocalin expression by co-stimulation with interleukin-17 and tumor necrosis factor-alpha is controlled by IkappaB-zeta but neither by C/EBP-beta nor C/EBP-delta.
J Biol Chem. 2010; 285(19):14088-100 [PubMed] Free Access to Full Article Related Publications
Neutrophil gelatinase-associated lipocalin (NGAL) is a siderophore-binding antimicrobial protein that is up-regulated in epithelial tissues during inflammation. We demonstrated previously that the gene encoding NGAL (LCN2) is strongly up-regulated by interleukin (IL)-1beta in an NF-kappaB-dependent manner but not by tumor necrosis factor (TNF)-alpha, another potent activator of NF-kappaB. This is due to an IL-1beta-specific synthesis of the NF-kappaB-binding co-factor IkappaB-zeta, which is essential for NGAL induction. We demonstrate here that NGAL is strongly induced by stimulation with TNF-alpha in the presence of IL-17, a pro-inflammatory cytokine produced by the newly discovered subset of CD4(+) T helper cells, T(H)-17. In contrast to the murine NGAL orthologue, 24p3/lipocalin 2, we found no requirement for C/EBP-beta or C/EBP-delta for NGAL induction by IL-17 and TNF-alpha as neither small interfering RNAs against the two C/EBP mRNAs nor mutation of the C/EBP sites in the LCN2 promoter abolished IL-17- and TNF-alpha-induced up-regulation of NGAL. NGAL induction is governed solely by NF-kappaB and its co-factor IkappaB-zeta. This was demonstrated by a pronounced reduction in the amount of NGAL mRNA and NGAL protein synthesized in cells treated with small interfering RNA against IkappaB-zeta and a total lack of activation of an LCN2 promoter construct with a mutated NF-kappaB site. As IL-17 stimulation stabilizes the IkappaB-zeta transcript, we propose a model where TNF-alpha induces activation and binding of NF-kappaB to the promoters of both NFKBIZ and LCN2 genes but induce only transcription of IkappaB-zeta. Co-stimulation with IL-17 leads to accumulation of IkappaB-zeta mRNA and IkappaB-zeta protein, which can bind to NF-kappaB on the LCN2 promoter and thus induce NGAL expression.

Silva FP, Swagemakers SM, Erpelinck-Verschueren C, et al.
Gene expression profiling of minimally differentiated acute myeloid leukemia: M0 is a distinct entity subdivided by RUNX1 mutation status.
Blood. 2009; 114(14):3001-7 [PubMed] Related Publications
Minimally differentiated acute myeloid leukemia (AML-M0) is defined by immature morphology and expression of early hematologic markers. By gene expression profiling (GEP) and subsequent unsupervised analysis of 35 AML-M0 samples and 253 previously reported AML cases, we demonstrate that AML-M0 cases express a unique signature that is largely separated from other molecular subtypes. Hematologic transcription regulators such as CEBPA, CEBPD, and ETV6, and the differentiation associated gene MPO appeared strongly down-regulated, in line with the primitive state of this leukemia. AML-M0 frequently carries loss-of-function RUNX1 mutation. Unsupervised analyses revealed a subdivision between AML-M0 cases with and without RUNX1 mutations. RUNX1 mutant AML-M0 samples showed a distinct up-regulation of B cell-related genes such as members of the B-cell receptor complex, transcription regulators RUNX3, ETS2, IRF8, or PRDM1, and major histocompatibility complex class II genes. Importantly, prediction with high accuracy of the AML-M0 subtype and prediction of patients carrying RUNX1 mutation within this subtype were possible based on the expression level of only a few transcripts. We propose that RUNX1 mutations in this AML subgroup cause lineage infidelity, leading to aberrant coexpression of myeloid and B-lymphoid genes. Furthermore, our results imply that AML-M0, although originally determined by morphology, constitutes a leukemia subgroup.

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