Treatment with bevacizumab (BEV) upregulates expression of the transcription factor Sp1 and its downstream target genes in human carcinoid cells: Molecular basis of the synergistic antiangiogenic activity of bevacizumab and mithramycin A (MIT)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15031-15031 ◽  
Author(s):  
J. Zhang ◽  
Z. Jia ◽  
L. Wang ◽  
Q. Li ◽  
L. Xiangdong ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Growth Factor ◽  
Nude Mice ◽  
Target Genes ◽  
Critical Role ◽  
Angiogenic Factors ◽  
Downstream Target ◽  
Transcription Factor Sp1 ◽  
Mithramycin A ◽  
The Impact

15031 Background: Our previous studies show that human carcinoid cells overexpress pro-angiogenic factors, vascular endothelial growth factor A (VEGF), and transcription factor Sp1 plays a critical role in VEGF inducible and constitutive expression. However, the impact of antiangiogenic therapy on the Sp1/VEGF pathway remains unclear. Method: Groups of 10 athymic BALB/c nude mice were implanted with 1.5 million human H727 carcinoid cells. Treatment with VEGF neutralizing monoclonal antibody, BEV, MIT, or BEV + MIT was initiated once implanted tumor reached 4 mm in size. Result: Treatment with BEV, suppressed human carcinoid growth in nude mice (tumor size at week 5 1280 mm3 vs 480 mm3; p < 0.001). Gene expression analyses revealed that this treatment substantially upregulated the expression of Sp1 (7 folds) and its downstream target genes, including VEGF (5 folds) and epidermal growth factor receptor (4 folds), in tumor tissues, whereas it did not have this effect on carcinoid cells in culture. Treatment with mithramycin A, an Sp1 inhibitor, suppressed the expression of Sp1 and its downstream target genes in both cell culture and tumors growing in nude mice. Median survival of mice treated with PBS, BEV, MIT, and BEV + MIT groups were 88, 112, 121, and >160 days respectively (p < 0.001). Combined treatment with bevacizumab and mithramycin A produced synergistic tumor suppression, which was consistent with suppression of the expression of Sp1 and its downstream target genes. Conclusion: Treatment with bevacizumab may block VEGF function but activate the pathway of its expression via positive feedback. Given the fact that Sp1 is an important regulator of the expression of multiple angiogenic factors, bevacizumab-initiated upregulation of Sp1 and subsequent overexpression of its downstream target genes may affect the potential angiogenic phenotype and effectiveness of antiangiogenic strategies for human carcinoid. No significant financial relationships to disclose.

A novel fibroblast growth factor gene expressed in the developing nervous system is a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx1

Development ◽  
1997 ◽  
Vol 124 (17) ◽  
pp. 3221-3232 ◽  
Author(s):  
J.R. McWhirter ◽  
M. Goulding ◽  
J.A. Weiner ◽  
J. Chun ◽  
C. Murre
Keyword(s):  
Nervous System ◽  
Transcription Factor ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Target Genes ◽  
Representational Difference Analysis ◽  
Bhlh Transcription Factor ◽  
Fibroblast Growth ◽  
Downstream Target ◽  
Developing Nervous System

Pbx1 is a homeodomain transcription factor that has the ability to form heterodimers with homeodomain proteins encoded by the homeotic selector (Hox) gene complexes and increase their DNA-binding affinity and specificity. A current hypothesis proposes that interactions with Pbx1 are necessary for Hox proteins to regulate downstream target genes that in turn control growth, differentiation and morphogenesis during development. In pre B cell leukemias containing the t(1;19) chromosome translocation, Pbx1 is converted into a strong transactivator by fusion to the activation domain of the bHLH transcription factor E2A. The E2A-Pbx1 fusion protein should therefore activate transcription of genes normally regulated by Pbx1. We have used the subtractive process of representational difference analysis to identify targets of E2A-Pbx1. We show that E2A-Pbx1 can directly activate transcription of a novel member of the fibroblast growth factor family of intercellular signalling molecules, FGF-15. The FGF-15 gene is expressed in a regionally restricted pattern in the developing nervous system, suggesting that FGF-15 may play an important role in regulating cell division and patterning within specific regions of the embryonic brain, spinal cord and sensory organs.

Fibroblast growth factor 21 (FGF-21) in obese children: no relationship to growth, IGF-1, and IGFBP-3

2016 ◽  
Vol 30 (2) ◽  
Author(s):  
Thomas Reinehr ◽  
Christian L. Roth ◽  
Joachim Woelfle
Keyword(s):  
Weight Loss ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Critical Role ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Obese Children ◽  
Pubertal Stage ◽  
The Impact ◽  
Igfbp 3

AbstractBackground:Fibroblast growth factor 21 (FGF-21) is a hepatic protein that plays a critical role in liver, adipose tissue, and bone metabolism. Animal models reported an increase of FGF-21 and associated growth disturbances in undernutrition. Therefore, we studied the impact of weight loss in obese children on growth, FGF-21, and insulin-like factor 1 (IGF-1) concentrations.Methods:We analyzed height, serum concentrations of FGF-21, IGF-1, IGFBP-3, leptin, and insulin at baseline and 1 year later in 30 obese children with substantial weight loss (reduction >0.5 BMI-SDS) and in 30 obese children of similar age, gender, and pubertal stage with stable BMI-SDS. All children participated in a 1-year lifestyle intervention. Height and IGF-1 was transformed to standard deviation score (SDS). Multiple linear regression analyses adjusted for age, gender, and pubertal stage were performed.Results:At baseline, height-SDS was significantly related to IGF-1-SDS (β-coefficient 0.68 95% confidence interval (95% CI)±0.49; p=0.008) and leptin (β-coefficient 0.042 95% CI±0.030; p=0.008), but not to FGF-21 or insulin. FGF-21 was not significantly associated with IGF-1 or IGFBP-3. In longitudinal analysis, changes of FGF-21 were not significantly related to changes of height, IGF-1-SDS or IGFBP-3. However, in the subgroup of 30 children with substantial BMI-SDS reduction, FGF-21, leptin, insulin, and HOMA decreased significantly.Conclusion:As there was no significant association between FGF-21 and growth or IGF-1 both in cross-sectional and longitudinal analyses, these findings do not support the hypothesis that FGF-21 is involved in growth of obese children. Further studies are necessary to understand the multiple alterations in the growth hormone (GH) axis in obese children.

Interaction of the transforming growth factor-β and Notch signaling pathways in the regulation of granulosa cell proliferation

2016 ◽  
Vol 28 (12) ◽  
pp. 1873 ◽  
Author(s):  
Xiao-Feng Sun ◽  
Xing-Hong Sun ◽  
Shun-Feng Cheng ◽  
Jun-Jie Wang ◽  
Yan-Ni Feng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
Growth Factor ◽  
Granulosa Cell ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Notch Pathway ◽  
Transforming Growth Factor Β ◽  
Notch Signalling ◽  
Signalling Pathways

The Notch and transforming growth factor (TGF)-β signalling pathways play an important role in granulosa cell proliferation. However, the mechanisms underlying the cross-talk between these two signalling pathways are unknown. Herein we demonstrated a functional synergism between Notch and TGF-β signalling in the regulation of preantral granulosa cell (PAGC) proliferation. Activation of TGF-β signalling increased hairy/enhancer-of-split related with YRPW motif 2 gene (Hey2) expression (one of the target genes of the Notch pathway) in PAGCs, and suppression of TGF-β signalling by Smad3 knockdown reduced Hey2 expression. Inhibition of the proliferation of PAGCs by N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butylester (DAPT), an inhibitor of Notch signalling, was rescued by both the addition of ActA and overexpression of Smad3, indicating an interaction between the TGF-β and Notch signalling pathways. Co-immunoprecipitation (CoIP) and chromatin immunoprecipitation (ChIP) assays were performed to identify the point of interaction between the two signalling pathways. CoIP showed direct protein–protein interaction between Smad3 and Notch2 intracellular domain (NICD2), whereas ChIP showed that Smad3 could be recruited to the promoter regions of Notch target genes as a transcription factor. Therefore, the findings of the present study support the idea that nuclear Smad3 protein can integrate with NICD2 to form a complex that acts as a transcription factor to bind specific DNA motifs in Notch target genes, such as Hey1 and Hey2, and thus participates in the transcriptional regulation of Notch target genes, as well as regulation of the proliferation of PAGCs.

scholarly journals The Caenorhabditis elegans Heterochronic Regulator LIN-14 Is a Novel Transcription Factor That Controls the Developmental Timing of Transcription from the Insulin/Insulin-Like Growth Factor Gene ins-33 by Direct DNA Binding

2005 ◽  
Vol 25 (24) ◽  
pp. 11059-11072 ◽  
Author(s):  
Marta Hristova ◽  
Darcy Birse ◽  
Yang Hong ◽  
Victor Ambros
Keyword(s):  
Transcription Factor ◽  
Caenorhabditis Elegans ◽  
Growth Factor ◽  
Dna Binding ◽  
Dna Sequences ◽  
Target Genes ◽  
Specific Gene ◽  
Insulin Like Growth Factor ◽  
Consensus Binding Site

ABSTRACT A temporal gradient of the novel nuclear protein LIN-14 specifies the timing and sequence of stage-specific developmental events in Caenorhabditis elegans. The profound effects of lin-14 mutations on worm development suggest that LIN-14 directly or indirectly regulates stage-specific gene expression. We show that LIN-14 can associate with chromatin in vivo and has in vitro DNA binding activity. A bacterially expressed C-terminal domain of LIN-14 was used to select DNA sequences that contain a putative consensus binding site from a pool of randomized double-stranded oligonucleotides. To identify candidates for genes directly regulated by lin-14, we employed DNA microarray hybridization to compare the mRNA abundance of C. elegans genes in wild-type animals to that in mutants with reduced or elevated lin-14 activity. Five of the candidate LIN-14 target genes identified by microarrays, including the insulin/insulin-like growth factor family gene ins-33, contain putative LIN-14 consensus sites in their upstream DNA sequences. Genetic analysis indicates that the developmental regulation of ins-33 mRNA involves the stage-specific repression of ins-33 transcription by LIN-14 via sequence-specific DNA binding. These results reinforce the conclusion that lin-14 encodes a novel class of transcription factor.

scholarly journals Deficiency of transcription factor RelB perturbs myeloid and DC development by hematopoietic-extrinsic mechanisms

2017 ◽  
Vol 114 (15) ◽  
pp. 3957-3962 ◽  
Author(s):  
Carlos G. Briseño ◽  
Marco Gargaro ◽  
Vivek Durai ◽  
Jesse T. Davidson ◽  
Derek J. Theisen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Critical Role ◽  
Radiation Chimeras ◽  
Severe Reduction ◽  
Myeloid Development ◽  
Noncanonical Pathway ◽  
Β Receptor ◽  
The Impact ◽  
Receptor Family

RelB is an NF-κB family transcription factor activated in the noncanonical pathway downstream of NF-κB–inducing kinase (NIK) and TNF receptor family members including lymphotoxin-β receptor (LTβR) and CD40. Early analysis suggested that RelB is required for classical dendritic cell (cDC) development based on a severe reduction of cDCs in Relb−/− mice associated with profound myeloid expansion and perturbations in B and T cells. Subsequent analysis of radiation chimeras generated from wild-type and Relb−/− bone marrow showed that RelB exerts cell-extrinsic actions on some lineages, but it has remained unclear whether the impact of RelB on cDC development is cell-intrinsic or -extrinsic. Here, we reevaluated the role of RelB in cDC and myeloid development using a series of radiation chimeras. We found that there was no cell-intrinsic requirement for RelB for development of most cDC subsets, except for the Notch2- and LTβR-dependent subset of splenic CD4+ cDC2s. These results identify a relatively restricted role of RelB in DC development. Moreover, the myeloid expansion in Relb−/− mice resulted from hematopoietic-extrinsic actions of RelB. This result suggests that there is an unrecognized but critical role for RelB within the nonhematopoietic niche that controls normal myelopoiesis.

Key Mechanisms of Early Lung Development

2007 ◽  
Vol 10 (5) ◽  
pp. 335-347 ◽  
Author(s):  
Jun Kimura ◽  
Gail H. Deutsch
Keyword(s):  
Respiratory Tract ◽  
Cell Fate ◽  
Target Genes ◽  
Critical Role ◽  
Hierarchical Classification ◽  
Branching Morphogenesis ◽  
Loss Of Function ◽  
Innovative Strategies ◽  
Downstream Target ◽  
Molecular Events

Lung morphogenesis requires the integration of multiple regulatory factors, which results in a functional air-blood interface required for gas exchange at birth. The respiratory tract is composed of endodermally derived epithelium surrounded by cells of mesodermal origin. Inductive signaling between these 2 tissue compartments plays a critical role in formation and differentiation of the lung, which is mediated by evolutionarily conserved signaling families used reiteratively during lung formation, including the fibroblast growth factor, hedgehog, retinoic acid, bone morphogenetic protein, and Wnt signaling pathways. Cells coordinate their response to these signaling proteins largely through transcription factors, which determine respiratory cell fate and pattern formation via the activation and repression of downstream target genes. Gain- and loss-of-function studies in null mutant and transgenic mice models have greatly facilitated the identification and hierarchical classification of these molecular programs. In this review, we highlight select molecular events that drive key phases of pulmonary development, including specification of a lung cell fate, primary lung bud formation, tracheoesophageal septation, branching morphogenesis, and proximal-distal epithelial patterning. Understanding the genetic pathways that regulate respiratory tract development is essential to provide insight into the pathogenesis of congenital anomalies and to develop innovative strategies to treat inherited and acquired lung disease.

scholarly journals Distinct Posttranscriptional Mechanisms Regulate the Activity of the Zn Finger Transcription Factor Lame duck during Drosophila Myogenesis

2006 ◽  
Vol 26 (4) ◽  
pp. 1414-1423 ◽  
Author(s):  
Hong Duan ◽  
Hanh T. Nguyen
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Posttranslational Modifications ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Protein Activity ◽  
Downstream Target ◽  
Muscle Formation ◽  
Lame Duck ◽  
Fusion Competent Myoblasts

ABSTRACT Skeletal muscle formation in Drosophila melanogaster requires two types of myoblasts, muscle founders and fusion-competent myoblasts. Lame duck (Lmd), a member of the Gli superfamily of transcription factors, is essential for the specification and differentiation of fusion-competent myoblasts. We report herein that appropriate levels of active Lmd protein are attained by a combination of posttranscriptional mechanisms. We provide evidence that two different regions of the Lmd protein are critical for modulating the balance between its nuclear translocation and its retention within the cytoplasm. Activation of the Lmd protein is also tempered by posttranslational modifications of the protein that do not detectably change its subcellular localization. We further show that overexpression of Lmd protein derivatives that are constitutively nuclear or hyperactive results in severe muscle defects. These findings underscore the importance of regulated Lmd protein activity in maintaining proper activation of downstream target genes, such as Mef2, within fusion-competent myoblasts.

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