scholarly journals dTcf/Pangolinsuppresses growth and tumor formation inDrosophila

2019 ◽  
Vol 116 (28) ◽  
pp. 14055-14064 ◽  
Author(s):  
Shilin Song ◽  
Diana Andrejeva ◽  
Flávia C. P. Freitas ◽  
Stephen M. Cohen ◽  
Héctor Herranz
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Normal Development ◽  
Tumor Development ◽  
Growth Control ◽  
Tissue Growth ◽  
Tumor Formation ◽  
Imaginal Disk ◽  
Animal Development ◽  
Transcription Factor 1

Wnt/Wingless (Wg) signaling controls many aspects of animal development and is deregulated in different human cancers. The transcription factor dTcf/Pangolin (Pan) is the final effector of the Wg pathway inDrosophilaand has a dual role in regulating the expression of Wg target genes. In the presence of Wg, dTcf/Pan interacts with β-catenin/Armadillo (Arm) and induces the transcription of Wg targets. In absence of Wg, dTcf/Pan partners with the transcriptional corepressor TLE/Groucho (Gro) and inhibits gene expression. Here, we use the wing imaginal disk ofDrosophilaas a model to examine the functions that dTcf/Pan plays in a proliferating epithelium. We report a function of dTcf/Pan in growth control and tumorigenesis. Our results show that dTcf/Pan can limit tissue growth in normal development and suppresses tumorigenesis in the context of oncogene up-regulation. We identify the conserved transcription factorsSox box protein 15(Sox15) andFtz transcription factor 1(Ftz-f1) as genes controlled by dTcf/Pan involved in tumor development. In conclusion, this study reports a role for dTcf/Pan as a repressor of normal and oncogenic growth and identifies the genes inducing tumorigenesis downstream of dTcf/Pan.

scholarly journals The miRNA bantam regulates growth and tumorigenesis by repressing the cell cycle regulator tribbles

2019 ◽  
Vol 2 (4) ◽  
pp. e201900381 ◽  
Author(s):  
Stephan U Gerlach ◽  
Moritz Sander ◽  
Shilin Song ◽  
Héctor Herranz
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Target Genes ◽  
Hippo Pathway ◽  
Growth Control ◽  
Tissue Growth ◽  
Tumor Formation ◽  
Hippo Signaling ◽  
Cell Cycle Regulators ◽  
The Hippo Pathway

One of the fundamental issues in biology is understanding how organ size is controlled. Tissue growth has to be carefully regulated to generate well-functioning organs, and defects in growth control can result in tumor formation. The Hippo signaling pathway is a universal growth regulator and has been implicated in cancer. In Drosophila, the Hippo pathway acts through the miRNA bantam to regulate cell proliferation and apoptosis. Even though the bantam targets regulating apoptosis have been determined, the target genes controlling proliferation have not been identified thus far. In this study, we identify the gene tribbles as a direct bantam target gene. Tribbles limits cell proliferation by suppressing G2/M transition. We show that tribbles regulation by bantam is central in controlling tissue growth and tumorigenesis. We expand our study to other cell cycle regulators and show that deregulated G2/M transition can collaborate with oncogene activation driving tumor formation.

scholarly journals NANOG expression in human development and cancerogenesis

2020 ◽  
Vol 245 (5) ◽  
pp. 456-464 ◽  
Author(s):  
Gašper Grubelnik ◽  
Emanuela Boštjančič ◽  
Ana Pavlič ◽  
Marina Kos ◽  
Nina Zidar
Keyword(s):  
Transcription Factor ◽  
Stem Cell ◽  
Human Development ◽  
Target Genes ◽  
Normal Development ◽  
Current Knowledge ◽  
Precancerous Lesions ◽  
Embryonic Stem ◽  
Predictive Marker ◽  
Nanog Expression

NANOG is an important stem cell transcription factor involved in human development and cancerogenesis. Its expression is complex and regulated on different levels. Moreover, NANOG protein might regulate hundreds of target genes at the same time. NANOG is crucial for preimplantation development phase and progressively decreases during embryonic stem cells differentiation, thus regulating embryonic and fetal development. Postnatally, NANOG is undetectable or expressed in very low amounts in the majority of human tissues. NANOG re-expression can be detected during cancerogenesis, already in precancerous lesions, with increasing levels of NANOG in high grade dysplasia. NANOG is believed to enable cancer cells to obtain stem-cell like properties, which are believed to be the source of expanding growth, tumor maintenance, metastasis formation, and tumor relapse. High NANOG expression in cancer is frequently associated with advanced stage, poor differentiation, worse overall survival, and resistance to treatment, and is therefore a promising prognostic and predictive marker. We summarize the current knowledge on the role of NANOG in cancerogenesis and development, including our own experience. We provide a critical overview of NANOG as a prognostic and diagnostic factor, including problems regarding its regulation and detection. Impact statement NANOG has emerged as a key stem cell transcription factor in normal development and cancerogenesis. It is generally regarded as a good prognostic and predictive factor in various human cancers. It is less known that it is expressed already at precancerous stages in various organs, suggesting that finally an ideal candidate diagnostic marker has been discovered, enabling to distinguish between true dysplasia and reactive atypia. NANOG regulation is complex, and new insights into our understanding of its regulation might provide important information for future development in a broad field of two entirely different processes, i.e. normal development and cancerogenesis, showing how a physiologic mechanism can be used and abused, transforming itself into a key mechanism of disease development and progression.

scholarly journals Identification of new octamer transcription factor 1‐target genes upregulated in castration‐resistant prostate cancer

2019 ◽  
Vol 110 (11) ◽  
pp. 3476-3485 ◽  
Author(s):  
Shinichiro Yamamoto ◽  
Ken‐ichi Takayama ◽  
Daisuke Obinata ◽  
Kyoko Fujiwara ◽  
Daisaku Ashikari ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transcription Factor ◽  
Target Genes ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Transcription Factor 1

scholarly journals Activating Transcription Factor 1 and CREB Are Important for Cell Survival during Early Mouse Development

2002 ◽  
Vol 22 (6) ◽  
pp. 1919-1925 ◽  
Author(s):  
Susanne C. Bleckmann ◽  
Julie A. Blendy ◽  
Dorothea Rudolph ◽  
A. Paula Monaghan ◽  
Wolfgang Schmid ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Mouse Development ◽  
Camp Response Element ◽  
Basic Leucine Zipper ◽  
Response Element ◽  
Activating Transcription Factor ◽  
Early Mouse ◽  
Transcription Factor 1

ABSTRACT Activating transcription factor 1 (ATF1), CREB, and the cyclic AMP (cAMP) response element modulatory protein (CREM), which constitute a subfamily of the basic leucine zipper transcription factors, activate gene expression by binding as homo- or heterodimers to the cAMP response element in regulatory regions of target genes. To investigate the function of ATF1 in vivo, we inactivated the corresponding gene by homologous recombination. In contrast to CREB-deficient mice, which suffer from perinatal lethality, mice lacking ATF1 do not exhibit any discernible phenotypic abnormalities. Since ATF1 and CREB but not CREM are strongly coexpressed during early mouse development, we generated mice deficient for both CREB and ATF1. ATF1−/− CREB−/− embryos die before implantation due to developmental arrest. ATF1+/− CREB−/− embryos display a phenotype of embryonic lethality around embryonic day 9.5 due to massive apoptosis. These results indicate that CREB and ATF1 act in concert to mediate signals essential for maintaining cell viability during early embryonic development.

scholarly journals Doublesex- and Mab-3-Related Transcription Factor-1 Repression of Aromatase Transcription, a Possible Mechanism Favoring the Male Pathway in Tilapia

Endocrinology ◽  
2010 ◽  
Vol 151 (3) ◽  
pp. 1331-1340 ◽  
Author(s):  
De-Shou Wang ◽  
Lin-Yan Zhou ◽  
Tohru Kobayashi ◽  
Masaru Matsuda ◽  
Yasushi Shibata ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Hek 293 ◽  
Aromatase Gene ◽  
Estrogen Production ◽  
Testicular Differentiation ◽  
Related Transcription Factor ◽  
Transcription Factor 1

Doublesex- and Mab-3-related transcription factor-1 (Dmrt1) is an important transcription factor implicated in early testicular differentiation in vertebrates, but its target genes are largely unknown. In the Nile tilapia, estrogen is the natural inducer of ovarian differentiation. Our recent studies have shown that Forkhead-l2 up-regulated transcription of the Cyp19a1a gene (aromatase) in the gonads in a female-specific manner. However, the upstream factor(s) down-regulating Cyp19a1a expression during testicular differentiation remains unclear. In the present study, we used in vitro (promoter analysis) and in vivo (transgenesis and in situ hybridization) approaches to examine whether Dmrt1 inhibits Cyp19a1a’s transcriptional activity. The in vitro analysis using luciferase assays revealed that Dmrt1 repressed basal as well as Ad4BP/SF-1-activated Cyp19a1a transcription in HEK 293 cells. Luciferase assays with various deletions of Dmrt1 also showed that the Doublesex and Mab-3 domain is essential for the repression. In vitro-translated Dmrt1 and the nuclear extract from tilapia testis could directly bind to the palindrome sequence ACATATGT in the Cyp19a1a promoter, as determined by EMSAs. Transgenic overexpression of Dmrt1 in XX fish resulted in decreased aromatase gene expression, reduced serum estradiol-17β levels, retardation of the ovarian cavity’s development, varying degrees of follicular degeneration, and even a partial to complete sex reversal. Our results indicate that aromatase is one of the targets of Dmrt1. Dmrt1 suppresses the female pathway by repressing aromatase gene transcription and estrogen production in the gonads of tilapia and possibly other vertebrates.

scholarly journals Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies

2019 ◽  
Author(s):  
Nélida Inés Noguera ◽  
Gianfranco Catalano ◽  
Cristina Banella ◽  
Mariadomenica Divona ◽  
Isabella Faraoni ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Target Genes ◽  
Therapeutic Potential ◽  
Synergistic Effects ◽  
Clonal Evolution ◽  
Growth Control ◽  
Treatment Strategies ◽  
Tissue Growth ◽  
Promyelocytic Leukemia ◽  
New Findings

In this review, we highlight new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in APL. PML-RARa sets the cellular landscape of Acute promyelocytic leukemia (APL) by repressing transcription of RARa target genes and disrupting PML-NBs. RAR receptors control the homeostasis of tissue growth, modeling and regeneration, PML NBs are involved in self-renewal of normal and cancer stem cells, DNA damage response, senescence and stress response. Additional somatic mutations in APL mainly involve FLT3, WT1, NRAS, KRAS, ARID1B and ARID1A genes. Treatment outcomes in patients with newly diagnosed APL improved dramatically since the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). ATRA activates the transcription of blocked genes and degrades PML-RARα, while ATO degrades PML-RARa by promoting apoptosis and has a pro-oxidant effect. Resistance to ATRA and ATO may derive from mutations in the RARa ligand binding domain (LBD) and in the PML-B2 domain of PML-RARa, but such mutations cannot explain the majority of resistances experienced in the clinic, globally accounting for 5-10% of cases. Several studies are ongoing to unravel clonal evolution and resistance, suggesting the therapeutic potential of new retinoid molecules and combinatorial treatments of ATRA or ATO with different drugs acting through alternative mechanisms of action, which may lead to synergistic effects on growth control or induction of apoptosis in APL cells.

scholarly journals RUNX1: an emerging therapeutic target for cardiovascular disease

2020 ◽  
Vol 116 (8) ◽  
pp. 1410-1423 ◽  
Author(s):  
Alexandra Riddell ◽  
Martin McBride ◽  
Thomas Braun ◽  
Stuart A Nicklin ◽  
Ewan Cameron ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Normal Development ◽  
Therapeutic Potential ◽  
Cardiac Remodelling ◽  
Cellular Mechanisms ◽  
Core Binding Factor ◽  
Multiple Systems ◽  
Binding Factor ◽  
Related Transcription Factor ◽  
Transcription Factor 1

Abstract Runt-related transcription factor-1 (RUNX1), also known as acute myeloid leukaemia 1 protein (AML1), is a member of the core-binding factor family of transcription factors which modulate cell proliferation, differentiation, and survival in multiple systems. It is a master-regulator transcription factor, which has been implicated in diverse signalling pathways and cellular mechanisms during normal development and disease. RUNX1 is best characterized for its indispensable role for definitive haematopoiesis and its involvement in haematological malignancies. However, more recently RUNX1 has been identified as a key regulator of adverse cardiac remodelling following myocardial infarction. This review discusses the role RUNX1 plays in the heart and highlights its therapeutic potential as a target to limit the progression of adverse cardiac remodelling and heart failure.

The bHLH transcription factor dHAND controls Sonic hedgehog expression and establishment of the zone of polarizing activity during limb development

Development ◽  
2000 ◽  
Vol 127 (11) ◽  
pp. 2461-2470 ◽  
Author(s):  
J. Charite ◽  
D.G. McFadden ◽  
E.N. Olson
Keyword(s):  
Transcription Factor ◽  
Sonic Hedgehog ◽  
Limb Development ◽  
Target Genes ◽  
Ectopic Expression ◽  
Tissue Growth ◽  
Limb Bud ◽  
Bhlh Transcription Factor ◽  
Expression Domain ◽  
Zone Of Polarizing Activity

Limb outgrowth and patterning of skeletal elements are dependent on complex tissue interactions involving the zone of polarizing activity (ZPA) in the posterior region of the limb bud and the apical ectodermal ridge. The peptide morphogen Sonic hedgehog (SHH) is expressed specifically in the ZPA and, when expressed ectopically, is sufficient to mimic its functions, inducing tissue growth and formation of posterior skeletal elements. We show that the basic helix-loop-helix transcription factor dHAND is expressed posteriorly in the developing limb prior to Shh and subsequently occupies a broad domain that encompasses the Shh expression domain. In mouse embryos homozygous for a dHAND null allele, limb buds are severely underdeveloped and Shh is not expressed. Conversely, misexpression of dHAND in the anterior region of the limb bud of transgenic mice results in formation of an additional ZPA, revealed by ectopic expression of Shh and its target genes, and resulting limb abnormalities that include preaxial polydactyly with duplication of posterior skeletal elements. Analysis of mouse mutants in which Hedgehog expression is altered also revealed a feedback mechanism in which Hedgehog signaling is required to maintain the full dHAND expression domain in the developing limb. Together, these findings identify dHAND as an upstream activator of Shh expression and important transcriptional regulator of limb development.

scholarly journals A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4–ERK5 axis

2015 ◽  
Vol 212 (10) ◽  
pp. 1571-1587 ◽  
Author(s):  
Ling Wu ◽  
Xing Chen ◽  
Junjie Zhao ◽  
Bradley Martin ◽  
Jarod A. Zepp ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Feedback Loop ◽  
Target Genes ◽  
Cell Metabolism ◽  
Tumor Formation ◽  
Basal Cells ◽  
Keratinocyte Proliferation ◽  
Inflammatory Microenvironment ◽  
Important Cytokine ◽  
Sustained Activation

Although IL-17 is emerging as an important cytokine in cancer promotion and progression, the underlining molecular mechanism remains unclear. Previous studies suggest that IL-17 (IL-17A) sustains a chronic inflammatory microenvironment that favors tumor formation. Here we report a novel IL-17–mediated cascade via the IL-17R–Act1–TRAF4–MEKK3–ERK5 positive circuit that directly stimulates keratinocyte proliferation and tumor formation. Although this axis dictates the expression of target genes Steap4 (a metalloreductase for cell metabolism and proliferation) and p63 (a transcription factor for epidermal stem cell proliferation), Steap4 is required for the IL-17–induced sustained expansion of p63+ basal cells in the epidermis. P63 (a positive transcription factor for the Traf4 promoter) induces TRAF4 expression in keratinocytes. Thus, IL-17–induced Steap4-p63 expression forms a positive feedback loop through p63-mediated TRAF4 expression, driving IL-17–dependent sustained activation of the TRAF4–ERK5 axis for keratinocyte proliferation and tumor formation.

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