FHL2

Gene Summary

Gene:FHL2; four and a half LIM domains 2
Aliases: DRAL, AAG11, FHL-2, SLIM3, SLIM-3
Location:2q12.2
Summary:This gene encodes a member of the four-and-a-half-LIM-only protein family. Family members contain two highly conserved, tandemly arranged, zinc finger domains with four highly conserved cysteines binding a zinc atom in each zinc finger. This protein is thought to have a role in the assembly of extracellular membranes. Also, this gene is down-regulated during transformation of normal myoblasts to rhabdomyosarcoma cells and the encoded protein may function as a link between presenilin-2 and an intracellular signaling pathway. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Aug 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:four and a half LIM domains protein 2
HPRD
Source:NCBIAccessed: 25 June, 2015

Ontology:

What does this gene/protein do?
Show (26)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

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

  • Gene Expression Regulation
  • Western Blotting
  • siRNA
  • Transcriptional Activation
  • DNA-Binding Proteins
  • Yeasts
  • Androgen Receptors
  • Protein Structure, Tertiary
  • Messenger RNA
  • Cancer Gene Expression Regulation
  • Protein Binding
  • Intracellular Signaling Peptides and Proteins
  • Promoter Regions
  • Colorectal Cancer
  • Cytoplasm
  • RTPCR
  • Neoplasm Proteins
  • Muscle Proteins
  • beta Catenin
  • LIM-Homeodomain Proteins
  • RHOA
  • Colonic Neoplasms
  • Prostate Cancer
  • Neoplastic Cell Transformation
  • Cell Nucleus
  • Wnt Proteins
  • p300-CBP Transcription Factors
  • Chromosome 2
  • Breast Cancer
  • Transcription Factors
  • Cell Proliferation
  • Mutation
  • Signal Transduction
  • Two-Hybrid System Techniques
  • Transfection
  • Cell Cycle
  • Base Sequence
  • Transcription
  • Apoptosis
  • Cell Movement
  • Homeodomain Proteins
Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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

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

Latest Publications: FHL2 (cancer-related)

Friedrichs J, Fink D, Mauch C, et al.
TGF-β1-dependent induction and nuclear translocation of FHL2 promotes keratin expression in pilomatricoma.
Virchows Arch. 2015; 466(2):199-208 [PubMed] Related Publications
Pilomatricoma is a tumour derived from hair matrix cells, which shows progressive keratin expression. Tumorigenesis is frequently associated with activating mutations in β-catenin gene inducing nuclear expression of β-catenin protein. The present study analysed the role of transforming growth factor-β1 (TGF-β1) and four-and-a-half LIM domain protein 2 (FHL2) in pilomatricoma in synopsis with their expression patterns in human anagen hair. Human anagen hair showed TGF-β1 and nuclear FHL2 expression in the outer root sheath layer separated from nuclear β-catenin staining, which was observed in cells of matrix and inner root sheath layers. Correspondingly, 41 out of 50 pilomatricomas showed co-labelling of TGF-β1 and nuclear FHL2 in tumour cells, which mostly lacked nuclear β-catenin expression. Tumoural proliferation (ki67) was associated with nuclear β-catenin staining but not with expression of nuclear FHL2. In early pilomatricomas, TGF-β1 expression was observed in few peripheral tumour cells showing absent or faint nuclear FHL2 co-staining. TGF-β1 expression extended in growing tumours going along with strong nuclear FHL2 co-labelling as well as progressive keratin 14 and keratin 1 expression. In vitro, cultured human keratinocytes showed weak to marked autocrine TGF-β1 expression; in case of enhanced TGF-β1 expression associated with keratin 10 staining. TGF-β1-treatment of cultured human keratinocytes induced nuclear and cytoplasmatic FHL2 staining as well as keratin 14 staining. Accordingly, siRNA-mediated FHL2 knockdown of TGF-β1-stimulated keratinocytes reduced keratin 14 staining. In conclusion, tumoural TGF-β1 secretion seems to induce nuclear translocation of co-factor FHL2 mediating progressive keratin expression in pilomatricoma.

Fan P, Cunliffe HE, Griffith OL, et al.
Identification of gene regulation patterns underlying both oestrogen- and tamoxifen-stimulated cell growth through global gene expression profiling in breast cancer cells.
Eur J Cancer. 2014; 50(16):2877-86 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
PURPOSE: A c-Src inhibitor blocks oestrogen (E2)-induced stress and converts E2 responses from inducing apoptosis to growth stimulation in E2-deprived breast cancer cells. A reprogrammed cell line, MCF-7:PF, results in a functional oestrogen receptor (ER). We addressed the question of whether the selective ER modulator 4-hydroxytamoxifen (4-OHT) could target ER to prevent E2-stimulated growth in MCF-7:PF cells.
METHODS: Expression of mRNA was measured through real-time RT-PCR. Global gene expression profile was analysed through microarray. Transcriptome profiles were screened by RNA-sequencing.
RESULTS: Unexpectedly, both 4-OHT and E2 stimulated cell growth in a concentration-dependent manner. Expression profiling showed a remarkable overlap in genes regulated in the same direction by E2 and 4-OHT. Pathway enrichment analysis of the 280 genes commonly deregulated in MCF-7:PF cells by 4-OHT and E2 revealed functions mainly related to membrane, cytoplasm and metabolic processes. Further analysis of 98 genes up-regulated by both 4-OHT and E2 uncovered a significant enrichment in genes associated with membrane remodelling, cytoskeleton reorganisation, cytoplasmic adapter proteins, cytoplasm organelle proteins and related processes. 4-OHT was more potent than E2 in up-regulating some membrane remodelling molecules, such as EHD2, FHL2, HOMER3 and RHOF. In contrast, 4-OHT acted as an antagonist to inhibit expression of the majority of enriched membrane-associated genes in wild-type MCF-7 cells.
CONCLUSIONS: Long-term selection pressure has changed the cell population responses to 4-OHT. Membrane-associated signalling is critical for 4-OHT-stimulated cell growth in MCF-7:PF cells. This study provides a rationale for the further investigation of target therapy for tamoxifen resistant patients.

Hou Y, Wang X, Li L, et al.
FHL2 regulates hematopoietic stem cell functions under stress conditions.
Leukemia. 2015; 29(3):615-24 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
FHL2, a member of the four and one half LIM domain protein family, is a critical transcriptional modulator. Here, we identify FHL2 as a critical regulator of hematopoietic stem cells (HSCs) that is essential for maintaining HSC self-renewal under regenerative stress. We find that Fhl2 loss has limited effects on hematopoiesis under homeostatic conditions. In contrast, Fhl2-null chimeric mice reconstituted with Fhl2-null bone marrow cells developed abnormal hematopoiesis with significantly reduced numbers of HSCs, hematopoietic progenitor cells (HPCs), red blood cells and platelets as well as hemoglobin levels. In addition, HSCs displayed a significantly reduced self-renewal capacity and were skewed toward myeloid lineage differentiation. We find that Fhl2 loss reduces both HSC quiescence and survival in response to regenerative stress, probably as a consequence of Fhl2-loss-mediated downregulation of cyclin-dependent kinase-inhibitors, including p21(Cip) and p27(Kip1). Interestingly, FHL2 is regulated under the control of a tissue-specific promoter in hematopoietic cells and it is downregulated by DNA hypermethylation in the leukemia cell line and primary leukemia cells. Furthermore, we find that downregulation of FHL2 frequently occurs in myelodysplastic syndrome and acute myeloid leukemia patients, raising a possibility that FHL2 downregulation has a role in the pathogenesis of myeloid malignancies.

Jachin S, Bae JS, Sung JJ, et al.
The role of nuclear EpICD in extrahepatic cholangiocarcinoma: association with β-catenin.
Int J Oncol. 2014; 45(2):691-8 [PubMed] Related Publications
After intramembranous proteolysis-mediated loss of the extracellular domain of the epithelial cell adhesion molecule (EpEx) and release of an intracellular domain (EpICD) into the cytoplasm, EpICD sequentially associates with FHL2 to form a nuclear complex with β-catenin and Lef-1. This association induces gene transcription involved in the activation of the oncogenic potential of epithelial cell adhesion molecule (EpCAM). We examined the localization and expression of EpEx, EpICD and β-catenin in surgical specimens of extrahepatic cholangiocarcinoma (ECC) from 79 patients and focused on the relationship between nuclear expression of EpICD and β-catenin. We also examined the role of EpICD by transfecting the EpICD cDNA in cholangiocarcinoma (CC) cell lines. There was a significant correlation between the nuclear expression of EpICD and β-catenin in ECC tissues. Frequent nuclear co-localization of EpICD and β-catenin was observed in cancer cells forming the invasive front. Nuclear expression of EpICD also significantly correlated with histologic grade of tumor. Overexpression of EpICD in the CC cells significantly increased the cell growth and proliferation. The overexpression of EpICD in the CC cells also increased the expression levels of the active form of β-catenin and EpCAM target genes, such as c-myc and cyclin D1. Furthermore, the overexpression of EpICD significantly enhanced the migration and invasiveness of CC cells. Conversely, the inhibition of EpCAM in EpCAM-overexpressing cells by siRNA significantly decreased cell proliferation, migration and invasion. These results indicate that the spatial localization of EpICD and its mutual interaction with β-catenin may be important in ECC progression and invasion.

Mhatre S, Madkaikar M, Jijina F, Ghosh K
Unusual clinical presentations of familial hemophagocytic lymphohistiocytosis type-2.
J Pediatr Hematol Oncol. 2014; 36(8):e524-7 [PubMed] Related Publications
BACKGROUND: Mutations of PRF1 gene have been identified in familial hemophagocytic lymphohistiocytosis type-2 (FHL-2) patients, and it has been reported as the commonest gene defect causing FHL. Patients with severe perforin deficiency usually present within first 1 year of life and with severe clinical manifestations.
OBSERVATION: We report 4 cases of severe perforin deficiency presenting with delayed onset and unusual clinical presentations viz., B-cell acute lymphoblastic leukemia, the Hodgkin lymphoma, tuberculosis, and the Still disease. Three of these 4 cases showed a common heterozygous missense mutation (p.Trp129Ser). Two of these patients expired because of uncontrolled hemophagocytic lymphohistiocytosis, one patient had 3 relapses while on therapy and one patient was in remission on maintenance therapy.
CONCLUSION: This study shows variety of clinical manifestations of perforin deficiency and although the onset of hemophagocytic lymphohistiocytosis is delayed in these patients, the outcome remains poor as in classical severe perforin deficiency patients.

Wu Y, Guo Z, Zhang D, et al.
A novel colon cancer gene therapy using rAAV‑mediated expression of human shRNA-FHL2.
Int J Oncol. 2013; 43(5):1618-26 [PubMed] Related Publications
FHL2 (Four and a half LIM-only protein 2) has been identified as an oncogene in colon cancer and suppression of FHL2 induces cell differentiation and tumorigenesis in colon cancer cell lines. The aim of this study was to develop a novel and effective approach to knockdown FHL2, which can serve as a promising target of colon cancer therapy. Recombinant adeno-associated virus (rAAV) was generated bearing with FHL2-shRNA and transfected into LoVo cells. Cell cycle and growth were assessed. The interaction between FHL2 and G0/G1 cell cycle and growth was evaluated by flow cytometry, western blot analysis and WST-1 assay. We showed that suppression of FHL2 by rAAV-shRNA induced G0/G1 cell cycle arrest and inhibited cell growth. Apoptosis-related proteins and their activity was investigated at the same time. rAAV-FHL2‑shRNA activated intrinsic and extrinsic apoptotic pathways and increased cell susceptibility to apoptotic stimuli by 5-FU. Moreover, a xenograft model was established to explore rAAV-FHL2-shRNA with 5-FU mediated tumorigenesis in vivo. A strong anti-tumorigenic effect of rAAV-FHL2-shRNA was shown in nude mice and this antitumor effect was enhanced when combined with 5-FU treatment. These findings implicate FHL2 as a cell cycle and growth modulator and thus inhibit apoptosis in colon cancer cells. rAAV-shRNA-FHL2 may serve as a novel and potent therapeutic or 5-FU co-therapeutic agent for colon cancer.

Dahan J, Nouët Y, Jouvion G, et al.
LIM-only protein FHL2 activates NF-κB signaling in the control of liver regeneration and hepatocarcinogenesis.
Mol Cell Biol. 2013; 33(16):3299-308 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Four-and-a-half LIM-only protein 2 (FHL2) is an important mediator in many signaling pathways. In this study, we analyzed the functions of FHL2 in nuclear factor κB (NF-κB) signaling in the liver. We show that FHL2 enhanced tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) activity in transcriptional activation of NF-κB targets by stabilizing the protein. TRAF6 is a binding partner of FHL2 and an important component of the Toll-like receptor-NF-κB pathway. Knockdown of FHL2 in 293-hTLR4/MD2-CD14 cells impaired lipopolysaccharide (LPS)-induced NF-κB activity, which regulates expression of inflammatory cytokines. Indeed, FHL2(-/-) macrophages showed significantly reduced production of TNF and interleukin 6 (IL-6) following LPS stimulation. TNF and IL-6 are the key cytokines that prime liver regeneration after hepatic injury. Following partial hepatectomy, FHL2(-/-) mice exhibited diminished induction of TNF and IL-6 and delayed hepatocyte regeneration. In the liver, NF-κB signaling orchestrates inflammatory cross talk between hepatocytes and hepatic immune cells that promote chemical hepatocarcinogenesis. We found that deficiency of FHL2 reduced susceptibility to diethylnitrosamine-induced hepatocarcinogenesis, correlating with the activator function of FHL2 in NF-κB signaling. Our findings demonstrate FHL2 as a positive regulator of NF-κB activity in liver regeneration and carcinogenesis and highlight the importance of FHL2 in both hepatocytes and hepatic immune cells.

Heemers HV
Identification of a RhoA- and SRF-dependent mechanism of androgen action that is associated with prostate cancer progression.
Curr Drug Targets. 2013; 14(4):481-9 [PubMed] Related Publications
Androgen receptor (AR) action is critical for prostate cancer (CaP) progression, but is not inhibited fully by available androgen deprivation therapy (ADT). One of the limitations to current ADT is that it targets all androgen action in CaP, and other, cells irrespective of clinical relevance. The resulting off-target effects are responsible for ADT associated side effects that affect negatively a patient's quality of life. Isolation of the AR-dependent events that drive CaP progression may lead to novel forms of ADT that are at least as effective but more selective. Here, an approach is described that starts from insights in the basic mechanism(s) by which AR regulates target gene expression to identify novel drugable targets downstream of AR. Exploration of the molecular events that underlie androgen regulation of the AR-associated coregulator FHL2 led to the isolation of a novel indirect mechanism of androgen action that is mediated by the secondary transcription factor Serum Response Factor (SRF). Using a combination of oligoarray and in silico analyses, an SRF-dependent fraction of AR action was identified that is enriched in CaP tissues, is able to discriminate between benign and malignant prostate, and correlates with aggressive disease and biochemical failure. The RhoA signaling axis, a well known upstream stimulator of SRF action that harbors drugable targets, conveyed androgen-responsiveness to SRF, and was activated in CaP where it correlates with increased CaP aggressiveness and poor outcome after surgery.

Brun J, Dieudonné FX, Marty C, et al.
FHL2 silencing reduces Wnt signaling and osteosarcoma tumorigenesis in vitro and in vivo.
PLoS One. 2013; 8(1):e55034 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: The molecular mechanisms that are involved in the growth and invasiveness of osteosarcoma, an aggressive and invasive primary bone tumor, are not fully understood. The transcriptional co-factor FHL2 (four and a half LIM domains protein 2) acts as an oncoprotein or as a tumor suppressor depending on the tissue context. In this study, we investigated the role of FHL2 in tumorigenesis in osteosarcoma model.
METHODOLOGY/PRINCIPAL FINDINGS: Western blot analyses showed that FHL2 is expressed above normal in most human and murine osteosarcoma cells. Tissue microarray analysis revealed that FHL2 protein expression is high in human osteosarcoma and correlates with osteosarcoma aggressiveness. In murine osteosarcoma cells, FHL2 silencing using shRNA decreased canonical Wnt/β-catenin signaling and reduced the expression of Wnt responsive genes as well as of the key Wnt molecules Wnt5a and Wnt10b. This effect resulted in inhibition of osteosarcoma cell proliferation, invasion and migration in vitro. Using xenograft experiments, we showed that FHL2 silencing markedly reduced tumor growth and lung metastasis occurence in mice. The anti-oncogenic effect of FHL2 silencing in vivo was associated with reduced cell proliferation and decreased Wnt signaling in the tumors.
CONCLUSION/SIGNIFICANCE: Our findings demonstrate that FHL2 acts as an oncogene in osteosarcoma cells and contributes to tumorigenesis through Wnt signaling. More importantly, FHL2 depletion greatly reduces tumor cell growth and metastasis, which raises the potential therapeutic interest of targeting FHL2 to efficiently impact primary bone tumors.

Jiang O, Zhou R, Wu D, et al.
CYP2E1 polymorphisms and colorectal cancer risk: a HuGE systematic review and meta-analysis.
Tumour Biol. 2013; 34(2):1215-24 [PubMed] Related Publications
Studies investigating the associations between Cytochrome P4502E1 (CYP2E1) polymorphisms and colorectal cancer (CRC) risk report conflicting results. We conducted a meta-analysis to assess the association between CYP2E1 gene Rsa I/Pst I, Dral T/A and 96-bp insertion polymorphisms and CRC susceptibility. Two investigators independently searched the Medline, Embase, CNKI, Wanfang, and Chinese Biomedicine Databases. Summary odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for CYP2E1 polymorphisms and CRC were calculated in a fixed-effect model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate. Ultimately, 12, 5, and 4 studies were found to be eligible for meta-analyses of Rsa I/Pst I, Dral T/A, and 96-bp insertion polymorphisms, respectively. Our analysis suggested that the variant genotype of Rsa I/Pst I were associated with a significantly increased CRC risk (c2/c2 vs. c1/c1, OR = 1.36, 95 % CI = 1.04-1.77; recessive model, OR = 1.35, 95 % CI = 1.04-1.75). Moreover, similar results were observed between CYP2E1 96-bp insertion polymorphism and CRC risk (dominant model, OR = 1.25, 95 % CI = 1.07-1.45), while no association was observed between CYP2E1 Dral T/A polymorphism and CRC susceptibility in any genetic model. No publication bias was found in the present study. This meta-analysis shows that CYP2E1 Rsa I/Pst I and 96-bp insertion polymorphisms may be associated with CRC risk. The CYP2E1 Dral T/A polymorphism was not detected to be related to the risk for CRC.

Chaar I, Amara S, Khiari M, et al.
Relationship between MDM2 and p53 alterations in colorectal cancer and their involvement and prognostic value in the Tunisian population.
Appl Immunohistochem Mol Morphol. 2013; 21(3):228-36 [PubMed] Related Publications
BACKGROUND: The prevalence of p53 mutations in colorectal cancer could reach 90%. The most important regulator of this protein that was identified originally was the Murine Double Minute2 (MDM2) oncoprotein, by which the levels of p53 were fixed through an autoregulatory feedback loop. In cancer cases, the overexpression of MDM2 deregulates this feedback, and the signaling pathway between MDM2 and p53 is blocked.
MATERIALS AND METHODS: We genotyped 167 patients and 167 healthy blood donors to determinate the mutational status of MDM2 and p53. Immunohistochemical analysis was performed on tumor and normal mucosa.
RESULTS: The MDM2 polymorphism study showed a higher distribution of MDM2 SNP309 in tumors compared with healthy controls. At the same time, the majority of samples with SNP309 indicated a positive expression of MDM2 protein in the tumor. In this case, we found a first significant association between p53 expression and the single-strand conformational polymorphism analysis and a second association between the MDM2 polymorphism and p53 mutation. Moreover, the nuclear overexpression of MDM2 and SNP309 was significantly related to a higher mortality rate.
CONCLUSIONS: In this work we wanted to highlight the role, which is becoming increasingly important, of MDM2. In fact, we conclude that the effects of MDM2 SNP309 may be considered a valuable prognostic marker to predict poor outcome for Tunisian patients with colorectal cancer.

Putnik M, Zhao C, Gustafsson JÅ, Dahlman-Wright K
Global identification of genes regulated by estrogen signaling and demethylation in MCF-7 breast cancer cells.
Biochem Biophys Res Commun. 2012; 426(1):26-32 [PubMed] Related Publications
Estrogen signaling and epigenetic modifications, in particular DNA methylation, are involved in regulation of gene expression in breast cancers. Here we investigated a potential regulatory cross-talk between these two pathways by identifying their common target genes and exploring underlying molecular mechanisms in human MCF-7 breast cancer cells. Gene expression profiling revealed that the expression of approximately 140 genes was influenced by both 17β-estradiol (E2) and a demethylating agent 5-aza-2'-deoxycytidine (DAC). Gene ontology (GO) analysis suggests that these genes are involved in intracellular signaling cascades, regulation of cell proliferation and apoptosis. Based on previously reported association with breast cancer, estrogen signaling and/or DNA methylation, CpG island prediction and GO analysis, we selected six genes (BTG3, FHL2, PMAIP1, BTG2, CDKN1A and TGFB2) for further analysis. Tamoxifen reverses the effect of E2 on the expression of all selected genes, suggesting that they are direct targets of estrogen receptor. Furthermore, DAC treatment reactivates the expression of all selected genes in a dose-dependent manner. Promoter CpG island methylation status analysis revealed that only the promoters of BTG3 and FHL2 genes are methylated, with DAC inducing demethylation, suggesting DNA methylation directs repression of these genes in MCF-7 cells. In a further analysis of the potential interplay between estrogen signaling and DNA methylation, E2 treatment showed no effect on the methylation status of these promoters. Additionally, we show that the ERα recruitment occurs at the FHL2 promoter in an E2- and DAC-independent fashion. In conclusion, we identified a set of genes regulated by both estrogen signaling and DNA methylation. However, our data does not support a direct molecular interplay of mediators of estrogen and epigenetic signaling at promoters of regulated genes.

Nouët Y, Dahan J, Labalette C, et al.
The four and a half LIM-only protein 2 regulates liver homeostasis and contributes to carcinogenesis.
J Hepatol. 2012; 57(5):1029-36 [PubMed] Related Publications
BACKGROUND & AIMS: The four and a half LIM-only protein 2 (FHL2) is upregulated in diverse pathological conditions. Here, we analyzed the effects of FHL2 overexpression in the liver of FHL2 transgenic mice (Apo-FHL2).
METHODS: We first examined cell proliferation and apoptosis in Apo-FHL2 livers and performed partial hepatectomy to investigate high FHL2 expression in liver regeneration. Expression of FHL2 was then analyzed by real time PCR in human hepatocellular carcinoma and adjacent non-tumorous livers. Finally, the role of FHL2 in hepatocarcinogenesis was assessed using Apo-FHL2;Apc(lox/lox) mice.
RESULTS: Six-fold increase in cell proliferation in transgenic livers was associated with concomitant apoptosis, resulting in normal liver mass. In Apo-FHL2 livers, both cyclin D1 and p53 were markedly increased. Evidence supporting a p53-dependent cell death mechanism was provided by the findings that FHL2 bound to and activated the p53 promoter, and that a dominant negative p53 mutant compromised FHL2-induced apoptosis in hepatic cells. Following partial hepatectomy in Apo-FHL2 mice, hepatocytes displayed advanced G1 phase entry and DNA synthesis leading to accelerated liver weight restoration. Interestingly, FHL2 upregulation in human liver specimens showed significant association with increasing inflammation score and cirrhosis. Finally, while Apo-FHL2 mice developed no tumors, the FHL2 transgene enhanced hepatocarcinogenesis induced by liver-specific deletion of the adenomatous polyposis coli gene and aberrant Wnt/β-catenin signaling in Apc(lox/lox) animals.
CONCLUSIONS: Our results implicate FHL2 in the regulation of signaling pathways that couple proliferation and cell death machineries, and underscore the important role of FHL2 in liver homeostasis and carcinogenesis.

Schmidt LJ, Duncan K, Yadav N, et al.
RhoA as a mediator of clinically relevant androgen action in prostate cancer cells.
Mol Endocrinol. 2012; 26(5):716-35 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Recently, we have identified serum response factor (SRF) as a mediator of clinically relevant androgen receptor (AR) action in prostate cancer (PCa). Genes that rely on SRF for androgen responsiveness represent a small fraction of androgen-regulated genes, but distinguish benign from malignant prostate, correlate with aggressive disease, and are associated with biochemical recurrence. Thus, understanding the mechanism(s) by which SRF conveys androgen regulation to its target genes may provide novel opportunities to target clinically relevant androgen signaling. Here, we show that the small GTPase ras homolog family member A (RhoA) mediates androgen-responsiveness of more than half of SRF target genes. Interference with expression of RhoA, activity of the RhoA effector Rho-associated coiled-coil containing protein kinase 1 (ROCK), and actin polymerization necessary for nuclear translocation of the SRF cofactor megakaryocytic acute leukemia (MAL) prevented full androgen regulation of SRF target genes. Androgen treatment induced RhoA activation, increased the nuclear content of MAL, and led to MAL recruitment to the promoter of the SRF target gene FHL2. In clinical specimens RhoA expression was higher in PCa cells than benign prostate cells, and elevated RhoA expression levels were associated with aggressive disease features and decreased disease-free survival after radical prostatectomy. Overexpression of RhoA markedly increased the androgen-responsiveness of select SRF target genes, in a manner that depends on its GTPase activity. The use of isogenic cell lines and a xenograft model that mimics the transition from androgen-stimulated to castration-recurrent PCa indicated that RhoA levels are not altered during disease progression, suggesting that RhoA expression levels in the primary tumor determine disease aggressiveness. Androgen-responsiveness of SRF target genes in castration-recurrent PCa cells continued to rely on AR, RhoA, SRF, and MAL and the presence of intact SRF binding sites. Silencing of RhoA, use of Rho-associated coiled-coil containing protein kinase 1 inhibitors, or an inhibitor of SRF-MAL interaction attenuated (androgen-regulated) cell viability and blunted PCa cell migration. Taken together, these studies demonstrate that the RhoA signaling axis mediates clinically relevant AR action in PCa.

Hubbi ME, Gilkes DM, Baek JH, Semenza GL
Four-and-a-half LIM domain proteins inhibit transactivation by hypoxia-inducible factor 1.
J Biol Chem. 2012; 287(9):6139-49 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that promotes angiogenesis, metabolic reprogramming, and other critical aspects of cancer biology. The four-and-a-half LIM domain (FHL) proteins are a family of LIM domain-only proteins implicated in transcriptional regulation and suppression of tumor growth. Here we describe functional interactions between the FHL proteins and HIF-1. FHL1-3 inhibit HIF-1 transcriptional activity and HIF-1α transactivation domain function by oxygen-independent mechanisms. FHL2 directly interacts with HIF-1α to repress transcriptional activity. FHL1 binds to the p300/CBP co-activators and disrupts binding with HIF-1α. FHL3 does not bind to HIF-1α or p300, indicating that it regulates transactivation by a novel molecular mechanism. Expression of the FHL proteins increased upon HIF-1α induction, suggesting the existence of a feedback loop. These results identify FHL proteins as negative regulators of HIF-1 activity, which may provide a mechanism by which they suppress tumor growth.

Zakariyah A, Hou W, Slim R, Jerome-Majewska L
TMED2/p24β1 is expressed in all gestational stages of human placentas and in choriocarcinoma cell lines.
Placenta. 2012; 33(3):214-9 [PubMed] Related Publications
Members of the transmembrane emp24 domain (Tmed)/p24 family of proteins are required for transport of proteins between the endoplasmic reticulum and the Golgi. One member of this family, Tmed2/p24β1, is expressed during placental development in mice and its expression is required for normal development of the labyrinth layer. Although TMED2 is conserved in humans, little is known about its expression and function in human placenta. We examined TMED2 expression in human placenta between 5.5 and 40 weeks of gestation and showed that TMED2 is expressed in syncytiotrophoblast, cytotrophoblast, and stromal cells. We also found high levels of TMED2 expression in BeWo but not in JEG-3 choriocarcinoma cell line. We used the BeWo cell line to determine TMED2 subcellular localization in placental cells and show its co-localization with the endoplasmic reticulum Golgi intermediate compartment. Our findings show conservation of TMED2 expression in human placenta and suggest that this protein may also play a role during placental development in humans.

Slim R, Coullin P, Diatta AL, et al.
NLRP7 and the genetics of post-molar choriocarcinomas in Senegal.
Mol Hum Reprod. 2012; 18(1):52-6 [PubMed] Related Publications
Gestational choriocarcinomas are malignant tumors of trophoblastic cells that affect 5-25% of women with sporadic hydatidiform moles (HMs) depending on countries and studies. Nucleotide binding and oligomerization domain-like receptor protein 7 (NLRP7) is a major gene responsible for recurrent HMs and recently mutations in this gene have also been shown in 13% of women with sporadic, non-recurrent  moles. To investigate the role of NLRP7 in the genetic susceptibility for the malignant degeneration of moles, we sequenced its 11 exons in 43 Senegalese patients with post-molar choriocarcinomas. We report the presence of three novel NLRP7 variants that were found only in patients but not in 100 controls from the Senegalese general population, 100 controls from the Tunisian general population, and 100 controls from the Canadian population. In addition, this analysis revealed significant differences in the frequencies of four non-synonymous NLRP7 variants between European and Senegalese controls with the biggest difference being for variant G487E present at a minor allele frequency of 3.5% in Europeans, 18.1% in Tunisians and 45.6% in Senegalese. Comparing human NLRP7 and its paralog, NLRP2, with their mammalian counterparts revealed that allele E at position 487 is most likely the ancestral allele that was acquired in Africa but driven to low frequencies in Europeans and Asians due to migration, population bottlenecks and selective pressures. This study is the first attempt to investigate the role of NLRP7 in choriocarcinomas and highlights the higher frequencies of NLRP7 variants in the general Senegalese and Tunisian populations both known to have higher frequencies of moles and choriocarcinomas.

Khiari M, Arfaoui A, Kriaa L, et al.
The prognostic value of the immunohistochemical expression and mutational pattern of the key mediator of Wnt signaling: beta-catenin in Tunisian patients with colorectal carcinoma.
Appl Immunohistochem Mol Morphol. 2012; 20(1):62-70 [PubMed] Related Publications
Beta-catenin plays a critical role with E-cadherin in cell-cell adhesion and is also a key molecule of the highly conserved Wnt signaling pathway that regulates cell proliferation and differentiation. Abrogation of this pathway is implicated in the carcinogenesis of several malignancies, especially colorectal cancer. The objective of this study was to determine the prognostic value of β-catenin/E-cadherin complex in Tunisian patients with colorectal cancer. Matched primary tumors from 150 patients with sporadic colorectal adenocarcinomas were stained for β-catenin and E-cadherin by using immunohistochemistry. Deletion of exon 3 of CTNNB1 gene was performed by polymerase chain reaction. Our results showed that β-catenin and E-cadherin expressions were related inversely to tumor differentiation. Furthermore, the nuclear expression of β-catenin was considerably increased in advanced colorectal adenocarcinomas and was highly associated with shorter survival of patients. Deletion of exon 3 of CTNNB1 was identified in 2 cases by using polymerase chain reaction and was significantly related to tumor invasion and aberrant expression of E-cadherin. The major finding of this study is that activation of β-catenin gene by deletions involving exon 3 may be considered as an advanced event in colorectal tumorigenesis in Tunisian patients, in contrast to some worldwide studies. Moreover, disruption of β-catenin/E-cadherin complex may be considered as a dependent predictor of disease outcome.

Ng CF, Zhou WJ, Ng PK, et al.
Characterization of human FHL2 transcript variants and gene expression regulation in hepatocellular carcinoma.
Gene. 2011; 481(1):41-7 [PubMed] Related Publications
The four-and-a-half LIM protein 2 (FHL2) was originally identified to be expressed abundantly in the heart, as well as in a wide range of tissues demonstrated in various studies. The human FHL2 gene expresses different transcripts which are known to differ only in the 5'UTR region. However, little is known about the functional role of the different variants and the mechanism of gene regulation. In the present study, we characterized the different alternative spliced transcripts of FHL2 by in silico analysis and RT-PCR analysis. A novel transcript variant was identified. The FHL2 gene produces transcripts by different 5' exons, which may be responsible for tissue-specific regulation. To study the mechanism of FHL2 gene regulation, the potential promoter region was investigated. We have identified a functional promoter region upstream of the transcription start site. Deletion mutation analysis of 5' flanking region showed that the fragment from -138 to +292 bp have positive regulatory effect. We identified the binding sites of Pax-5/ZF5 in this region and found that Pax-5 and ZF5 expression in HCC samples had a significant positive correlation with FHL2 expression, suggesting a possible role for these transcription factors in the regulation of FHL2 expression.

Choufani S, Shapiro JS, Susiarjo M, et al.
A novel approach identifies new differentially methylated regions (DMRs) associated with imprinted genes.
Genome Res. 2011; 21(3):465-76 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Imprinted genes are critical for normal human growth and neurodevelopment. They are characterized by differentially methylated regions (DMRs) of DNA that confer parent of origin-specific transcription. We developed a new strategy to identify imprinted gene-associated DMRs. Using genome-wide methylation profiling of sodium bisulfite modified DNA from normal human tissues of biparental origin, candidate DMRs were identified by selecting CpGs with methylation levels consistent with putative allelic differential methylation. In parallel, the methylation profiles of tissues of uniparental origin, i.e., paternally-derived androgenetic complete hydatidiform moles (AnCHMs), and maternally-derived mature cystic ovarian teratoma (MCT), were examined and then used to identify CpGs with parent of origin-specific DNA methylation. With this approach, we found known DMRs associated with imprinted genomic regions as well as new DMRs for known imprinted genes, NAP1L5 and ZNF597, and novel candidate imprinted genes. The paternally methylated DMR for one candidate, AXL, a receptor tyrosine kinase, was also validated in experiments with mouse embryos that demonstrated Axl was expressed preferentially from the maternal allele in a DNA methylation-dependent manner.

Shaikhibrahim Z, Langer B, Lindstrot A, et al.
Ets-1 is implicated in the regulation of androgen co-regulator FHL2 and reveals specificity for migration, but not invasion, of PC3 prostate cancer cells.
Oncol Rep. 2011; 25(4):1125-9 [PubMed] Related Publications
Different members of the Ets-family of transcription factors are involved in TMPRSS-2-Ets translocations frequently found in human prostate cancers. We previously reported that Ets-1, which is the prototype of Ets-family members, promotes both migration and invasion of melanoma, Hela and glioma cells. Here, we examined whether Ets-1 has a similar effect upon migration and invasion of PC3 prostate cancer cells, and whether it is implicated in the regulation of the androgen co-regulator four and a half LIM only protein-2 (FHL2). Two stable PC3 cell cultures were established by transfection with either an Ets-1 inverse antisense expression vector or a mock control vector. Western blot analysis confirmed presence of Ets-1 in mock and absence in Ets-1 inverse cells. Microarray and qRT-PCR revealed an up-regulation of FHL2 in Ets-1 blocked cells, compared to mock. To examine the effects of Ets-1 upon cell migration, a wound assay was performed, and demonstrated that wounds were completely colonized by mock compared to Ets-1 blocked cells after 55 h. Evaluation of the effect upon invasion was examined using the Boyden chamber, which revealed no significant difference between mock and Ets-1 blocked cells. In conclusion, our study demonstrated for the first time that Ets-1 is implicated in the regulation of the androgen co-regulator FHL2, and reveals specificity of action for migration, but not invasion of PC3 prostate cancer cells.

Zhang W, Yang Y, Jiang B, et al.
XIAP-associated factor 1 interacts with and attenuates the trans-activity of four and a Half LIM protein 2.
Mol Carcinog. 2011; 50(3):199-207 [PubMed] Related Publications
XIAP-associated factor 1(XAF1) is a tumor suppressor with its functional mechanisms not fully understood. The zinc-finger cluster located at the N-terminus is the only domain structure. Four and a half LIM domain protein 2 (FHL2) also contains a tandem zinc finger structure, and its protein functions as an important adaptor and modifier in protein-protein interactions. Both of their structures are relatively simple, while the association between them is still unclear. In this study, we detected the interaction between XAF1 and FHL2 by using the yeast two-hybrid system. We identified FHL2 as a XAF1 binding protein. Furthermore, both XAF1 and FHL2 localized to the cytoplasm, mitochondria, and nucleus of gastric cancer cells. Over-expression of XAF1 excluded FHL2 from the nucleus and suppressed the trans-activity of FHL2 in stimulating the transcriptional activities of β-catenin and AP-1. In conclusion, our findings unraveled an antagonistic mechanism between a tumor suppressor and an oncoprotein in cancer cells.

Zhang W, Wang J, Zou B, et al.
Four and a half LIM protein 2 (FHL2) negatively regulates the transcription of E-cadherin through interaction with Snail1.
Eur J Cancer. 2011; 47(1):121-30 [PubMed] Related Publications
E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT), which plays a crucial role in cancer metastasis. We previously demonstrated that four and a half LIM protein 2 (FHL2) inhibited E-cadherin expression and promoted invasive potential and EMT in colon cancer. Here, we aim to further define the mechanism underlying the inhibition of E-cadherin by FHL2 in colon cancer. The expression profiles of FHL2 and Snail1 were first observed by Western blot, immunofluorescence and immunohistochemistry. We found that both the protein level and the cellular localisation of Snail1 were quite similar to FHL2 in colon cancer; reciprocal co-immunoprecipitation assay showed that FHL2 was able to bind Snail1 and its intact structure was required. The expression of FHL2 was positively correlated to Snail1 while negatively to E-cadherin and phospho-Snail1. FHL2 over-expression induced the accumulation of Snail1 in the nucleus. Moreover, dual luciferase assay revealed that FHL2 over-expression decreased while FHL2 siRNA increased the transcriptional activities of two E-cadherin promoter constructs which contained E-box sites (Snail1-binding elements). Mutation of E-boxes increased the transcriptional activities and FHL2 expression was involved in the function of mutation. These results suggested that FHL2 negatively regulated E-cadherin transcriptional activity through interaction with Snail1. Our study established a novel regulatory function of FHL2 and revealed a potential mechanism on promoting the process of EMT.

Xiong Z, Ding L, Sun J, et al.
Synergistic repression of estrogen receptor transcriptional activity by FHL2 and Smad4 in breast cancer cells.
IUBMB Life. 2010; 62(9):669-76 [PubMed] Related Publications
Four and a half LIM domain protein 2 (FHL2) has been implicated in development and progression of various types of cancers. However, little is known about the biological function of FHL2 in breast cancer. Here, we report that FHL2 physically and functionally interacts with estrogen receptors (ERα and ERβ), important regulators of breast cancer development and progression. The N-terminal half LIM domain or a single LIM domain of FHL2 was sufficient for its interaction with ERα and ERβ. Overexpression of FHL2 reduced ER transcriptional activity in breast cancer cells, whereas reduction of endogenous FHL2 with FHL2 small interfering RNA enhanced ER transactivation. Moreover, FHL2 cooperates with Smad4, a previously known corepressor for ERα, to inhibit ERα transcriptional activity as well as expression of the estrogen-responsive gene cathepsin D. The synergistic inhibition of ERα transcriptional activity by FHL2 and Smad4 may be due to enhanced interaction of Smad4 with ERα by FHL2, because FHL2(1-156), the FHL2 deletion mutant, which showed no synergistic effect, failed to increase such interaction. These data suggested the cooperative regulation of estrogen signaling by FHL2 and Smad4 in breast cancer cells, and might provide a new regulation mechanism underlying breast cancer development and progression.

Guo Z, Zhang W, Xia G, et al.
Sp1 upregulates the four and half lim 2 (FHL2) expression in gastrointestinal cancers through transcription regulation.
Mol Carcinog. 2010; 49(9):826-36 [PubMed] Related Publications
In this study, our purpose is to clarify the role of specificity protein 1 (Sp1) in transcription activation of the four and half lim 2 (FHL2). pLuc595 which contained -1163nt to -568nt upstream ATG starting codon displayed the highest while pLuc382 (-950nt to -568nt) displayed lowest transcription activities in GI cancer cells. Meanwhile, suppression of Sp1 by siRNA or chemical inhibitor, mithramycin A (MIT) inhibited the promoter activity and FHL2 expression. Bioinformatics analysis showed two putative Sp1 binding elements within pLuc595 while EMSA assay demonstrated that the wild type but not the mutated probe containing the distal element bound to the cell nuclear protein specifically. Mutation of the distal Sp1 binding sequence suppressed the transcription activity of pLuc595. In vivo study showed that both Sp1 and FHL2 were highly expressed by cancer cells but not the normal GI tissues with their expressions being positive correlated. These data identified a functional Sp1 positively regulatory element (-1058nt to -1049nt) within FHL2 promoter, and the positive correlation between Sp1 and FHL2 in expressing pattern and signal mechanism strongly suggested their synergized effect in carcinogenesis and progression of GI cancers.

Labalette C, Nouët Y, Levillayer F, et al.
Deficiency of the LIM-only protein FHL2 reduces intestinal tumorigenesis in Apc mutant mice.
PLoS One. 2010; 5(4):e10371 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: The four and a half LIM-only protein 2 (FHL2) is capable of shuttling between focal adhesion and nucleus where it signals through direct interaction with a number of proteins including beta-catenin. Although FHL2 activation has been found in various human cancers, evidence of its functional contribution to carcinogenesis has been lacking.
METHODOLOGY/PRINCIPAL FINDINGS: Here we have investigated the role of FHL2 in intestinal tumorigenesis in which activation of the Wnt pathway by mutations in the adenomatous polyposis coli gene (Apc) or in beta-catenin constitutes the primary transforming event. In this murine model, introduction of a biallelic deletion of FHL2 into mutant Apc(Delta14/+) mice substantially reduces the number of intestinal adenomas but not tumor growth, suggesting a role of FHL2 in the initial steps of tumorigenesis. In the lesions, Wnt signalling is not affected by FHL2 deficiency, remaining constitutively active. Nevertheless, loss of FHL2 activity is associated with increased epithelial cell migration in intestinal epithelium, which might allow to eliminate more efficiently deleterious cells and reduce the risk of tumorigenesis. This finding may provide a mechanistic basis for tumor suppression by FHL2 deficiency. In human colorectal carcinoma but not in low-grade dysplasia, we detected up-regulation and enhanced nuclear localization of FHL2, indicating the activation of FHL2 during the development of malignancy.
CONCLUSIONS/SIGNIFICANCE: Our data demonstrate that FHL2 represents a critical factor in intestinal tumorigenesis.

Lu G, Xie ZD, Shen KL, et al.
Mutations in the perforin gene in children with hemophagocytic lymphohistiocytosis.
Chin Med J (Engl). 2009; 122(23):2851-5 [PubMed] Related Publications
BACKGROUND: Recent studies have reported germline mutations in the perforin gene (PRF1) in some types of hemophagocytic lymphohistiocytosis (HLH). However, the prevalence of PRF1 mutations in HLH in Chinese pediatric patients has not been extensively studied. The aim of this study was to investigate the prevalence of mutations and sequence variations in the PRF1 gene in Chinese pediatric patients with HLH.
METHODS: Polymerase chain reaction (PCR) was performed with five pairs of primers for the coding exons and the flanking intron sequences of PRF1. Sequencing of PCR products was subsequently applied in 30 pediatric patients with HLH and in 50 controls.
RESULTS: Three heterozygous mutations in a coding region were found, which resulted in amino acid changes (C102F, S108N and T450M) in three patients. These mutations were not detected in control subjects. One patient had compound heterozygous mutations (S108N and T450M) in PRF1 as the background defect, and documented familial HLH type 2 (FHL2). One synonymous sequence variant (Q540Q) was observed in one patient but not in the controls. Two SNPs (A274A, H300H) in the coding region were detected in HLH patients and controls, but without differences in the heterozygosity rate between the two groups (P > 0.05 for all comparisons).
CONCLUSIONS: We have identified three patients with three heterozygous missense mutations in PRF1; two of those three mutations (C102F and S108N) have so far been found only from Chinese patients. These findings are useful in evaluating the prevalence of PRF1 mutations in Chinese pediatric patients with HLH, and to correlate their genotype with phenotype. Some patients without familial history probably have primary HLH, which should be suspected even beyond the usual age range.

Werdin F, Peek A, Martin NC, Baumeister S
Superior gluteal artery perforator flap in bilateral breast reconstruction.
Ann Plast Surg. 2010; 64(1):17-21 [PubMed] Related Publications
The incidence of bilateral breast reconstruction is increasing particularly due to genetic counseling and the option for bilateral prophylactic mastectomies. The decision to undergo a prophylactic mastectomy depends on the achievable outcomes of breast reconstruction. The free superior gluteal artery perforator flap (sGAP) flap is one option for autologous bilateral reconstruction which has rarely been reported.All bilateral sGAP flaps performed in the department of plastic surgery at the Behandlungszentrum Vogtareuth over a period of 4.5 years were retrospectively analyzed for indication, success rate, and complications.Thirty sGAP flaps were performed for bilateral breast reconstruction. The average age of the 15 women was 42 years and the average body mass index was 20.8. Indications for breast reconstruction were predominantly prophylactic mastectomies (60%). Indication for a sGAP flap was either a thin patient with insufficient abdominal tissue or a 2-staged bilateral reconstruction. 83% of the breast reconstructions were performed secondarily and 93% in 2 stages. The average operating time was 7 hours 12 minutes. Twenty-nine flaps (97%) were successful. Complications were fat necrosis (n = 3), hematoma (n = 3), and breast seroma (n = 1). Donor site complications were seroma (n = 8), infection (n = 1), and wound dehiscence (n = 1).Our results with bilateral breast reconstruction with the sGAP flap show cosmetically appealing results with high success and low complication rates on the breast. However, seromas on the donor site occurred in 27%. In addition, the sGAP flap is a technically demanding and time consuming operation. We recommend the sGAP flap when the abdomen has not enough tissue bulk to perform a deep inferior epigastric perforator flap or for a 2-staged bilateral reconstruction. This is often the case in women with a hereditary high risk of breast cancer who often present as young and slim patients.

Qian Z, Joslin JM, Tennant TR, et al.
Cytogenetic and genetic pathways in therapy-related acute myeloid leukemia.
Chem Biol Interact. 2010; 184(1-2):50-7 [PubMed] Related Publications
Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/t-AML) are late complications of cytotoxic therapy used in the treatment of malignant diseases. The most common subtype of t-AML ( approximately 75% of cases) develops after exposure to alkylating agents, and is characterized by loss or deletion of chromosome 5 and/or 7 [-5/del(5q), -7/del(7q)], and a poor outcome (median survival 8 months). In the University of Chicago's series of 386 patients with t-MDS/t-AML, 79 (20%) patients had abnormalities of chromosome 5, 95 (25%) patients had abnormalities of chromosome 7, and 85 (22%) patients had abnormalities of both chromosomes 5 and 7. t-MDS/t-AML with a -5/del(5q) is associated with a complex karyotype, characterized by trisomy 8, as well as loss of 12p, 13q, 16q22, 17p (TP53 locus), chromosome 18, and 20q. In addition, this subtype of t-AML is characterized by a unique expression profile (higher expression of genes) involved in cell cycle control (CCNA2, CCNE2, CDC2), checkpoints (BUB1), or growth (MYC), loss of expression of IRF8, and overexpression of FHL2. Haploinsufficiency of the RPS14, EGR1, APC, NPM1, and CTNNA1 genes on 5q has been implicated in the pathogenesis of MDS/AML. In previous studies, we determined that Egr1 acts by haploinsufficiency and cooperates with mutations induced by alkylating agents to induce myeloid leukemias in the mouse. To identify mutations that cooperate with Egr1 haploinsufficiency, we used retroviral insertional mutagenesis. To date, we have identified two common integration sites involving genes encoding transcription factors that play a critical role in hematopoiesis (Evi1 and Gfi1b loci). Of note is that the EVI1 transcription factor gene is deregulated in human AMLs, particularly those with -7, and abnormalities of 3q. Identifying the genetic pathways leading to t-AML will provide new insights into the underlying biology of this disease, and may facilitate the identification of new therapeutic targets.

Han W, Wu Z, Zhao Y, et al.
FHL2 interacts with and acts as a functional repressor of Id2 in human neuroblastoma cells.
Nucleic Acids Res. 2009; 37(12):3996-4009 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Inhibitor of differentiation 2 (Id2) is a natural inhibitor of the basic helix-loop-helix transcription factors. Although Id2 is well known to prevent differentiation and promote cell-cycle progression and tumorigenesis, the molecular events that regulate Id2 activity remain to be investigated. Here, we identified that Four-and-a-half LIM-only protein 2 (FHL2) is a novel functional repressor of Id2. Moreover, we demonstrated that FHL2 can directly interact with all members of the Id family (Id1-4) via an N-terminal loop-helix structure conserved in Id proteins. FHL2 antagonizes the inhibitory effect of Id proteins on basic helix-loop-helix protein E47-mediated transcription, which was abrogated by the deletion mutation of Ids that disrupted their interaction with FHL2. We also showed a competitive nature between FHL2 and E47 for binding Id2, whereby FHL2 prevents the formation of the Id2-E47 heterodimer, thus releasing E47 to DNA and restoring its transcriptional activity. FHL2 expression was remarkably up-regulated during retinoic acid-induced differentiation of neuroblastoma cells, during which the expression of Id2 was opposite to that. Ectopic FHL2 expression in neuroblastoma cells markedly reduces the transcriptional and cell-cycle promoting functions of Id2. Altogether, these results indicate that FHL2 is an important repressor of the oncogenic activity of Id2 in neuroblastoma cells.

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