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Alba Maiques-Diaz, Gary J Spencer, James T Lynch, Filippo Ciceri, Emma L Williams, Fabio M R Amaral, Daniel H Wiseman, William J Harris, Yaoyong Li, Sudhakar Sahoo, James R Hitchin, Daniel P Mould, Emma E Fairweather, Bohdan Waszkowycz, Allan M Jordan, Duncan L Smith, Tim C P Somervaille
Pharmacologic inhibition of LSD1 promotes blast cell differentiation in acute myeloid leukemia (AML) with MLL translocations. The assumption has been that differentiation is induced through blockade of LSD1's histone demethylase activity. However, we observed that rapid, extensive, drug-induced changes in transcription occurred without genome-wide accumulation of the histone modifications targeted for demethylation by LSD1 at sites of LSD1 binding and that a demethylase-defective mutant rescued LSD1 knockdown AML cells as efficiently as wild-type protein...
March 27, 2018: Cell Reports
Matthew Velinder, Jason Singer, Diana Bareyan, Jessica Meznarich, Christopher M Tracy, James M Fulcher, David McClellan, Helena Lucente, Sarah Franklin, Sunil Sharma, Michael E Engel
No abstract text is available yet for this article.
August 11, 2017: Biochemical Journal
Shinji Takagi, Yoshinori Ishikawa, Akio Mizutani, Shinji Iwasaki, Satoru Matsumoto, Yusuke Kamada, Toshiyuki Nomura, Kazuhide Nakamura
T-3775440 is an irreversible inhibitor of the chromatin demethylase LSD1, which exerts antiproliferative effects by disrupting the interaction between LSD1 and GFI1B, a SNAG domain transcription factor, inducing leukemia cell transdifferentiation. Here, we describe the anticancer effects and mechanism of action of T-3775440 in small-cell lung cancer (SCLC). T-3775440 inhibited proliferation of SCLC cells in vitro and retarded SCLC tumor growth in vivo T-3775440 disrupted the interaction between LSD1 and the transcriptional repressor INSM1, thereby inhibiting expression of neuroendocrine-associated genes, such as ASCL1 INSM1 silencing phenocopied the effects of T-3775440 on gene expression and cell proliferation, consistent with the likelihood T-3775440 mediated its effects in SCLC by inhibiting INSM1...
September 1, 2017: Cancer Research
Ada A Dattoli, Mark A Hink, Timothy Q DuBuc, Bram J Teunisse, Joachim Goedhart, Eric Röttinger, Marten Postma
SNAIL transcriptional factors are key regulators during development and disease. They arose early during evolution, and in cnidarians such as Nematostella vectensis, NvSNAILA/B are detected in invaginating tissues during gastrulation. The function of SNAIL proteins is well established in bilaterians but their roles in cnidarians remain unknown. The structure of NvSNAILA and B is similar to the human SNAIL1 and 2, including SNAG and zinc-finger domains. Here, we performed a molecular analysis on localization and mobility of NvSNAILA/B using mammalian cells and Nematostella embryos...
July 20, 2015: Scientific Reports
Giovanna Ferrari-Amorotti, Claudia Chiodoni, Fei Shen, Sara Cattelani, Angela Rachele Soliera, Gloria Manzotti, Giulia Grisendi, Massimo Dominici, Francesco Rivasi, Mario Paolo Colombo, Alessandro Fatatis, Bruno Calabretta
Most triple-negative breast cancers (TNBCs) exhibit gene expression patterns associated with epithelial-to-mesenchymal transition (EMT), a feature that correlates with a propensity for metastatic spread. Overexpression of the EMT regulator Slug is detected in basal and mesenchymal-type TNBCs and is associated with reduced E-cadherin expression and aggressive disease. The effects of Slug depend, in part, on the interaction of its N-terminal SNAG repressor domain with the chromatin-modifying protein lysine demethylase 1 (LSD1); thus, we investigated whether tranylcypromine [also known as trans-2-phenylcyclopropylamine hydrochloride (PCPA) or Parnate], an inhibitor of LSD1 that blocks its interaction with Slug, suppresses the migration, invasion, and metastatic spread of TNBC cell lines...
December 2014: Neoplasia: An International Journal for Oncology Research
Jochen E Welcker, Luis R Hernandez-Miranda, Florian E Paul, Shiqi Jia, Andranik Ivanov, Matthias Selbach, Carmen Birchmeier
The Insm1 gene encodes a zinc finger factor expressed in many endocrine organs. We show here that Insm1 is required for differentiation of all endocrine cells in the pituitary. Thus, in Insm1 mutant mice, hormones characteristic of the different pituitary cell types (thyroid-stimulating hormone, follicle-stimulating hormone, melanocyte-stimulating hormone, adrenocorticotrope hormone, growth hormone and prolactin) are absent or produced at markedly reduced levels. This differentiation deficit is accompanied by upregulated expression of components of the Notch signaling pathway, and by prolonged expression of progenitor markers, such as Sox2...
December 2013: Development
José Manuel Mingot, Sonia Vega, Amparo Cano, Francisco Portillo, M Angela Nieto
Exportin5 mediates the nuclear export of double-stranded RNAs, including pre-microRNAs, adenoviral RNAs, and tRNAs. When tRNAs are aminoacylated, the Exportin5-aminoacyl (aa)-tRNA complex recruits and coexports the translation elongation factor eEF1A. Here, we show that eEF1A binds to Snail transcription factors when bound to their main target, the E-cadherin promoter, facilitating their export to the cytoplasm in association with the aa-tRNA-Exportin5 complex. Snail binds to eEF1A through the SNAG domain, a protein nuclear export signal present in several transcription factor families, and this binding is regulated by phosphorylation...
November 14, 2013: Cell Reports
Yifan Wang, Jian Shi, Kequn Chai, Xuhua Ying, Binhua P Zhou
Epithelial-mesenchymal transition (EMT) is a highly conserved process in which polarized, immobile epithelial cells lose tight junctions, associated adherence, and become migratory mesenchymal cells. Several transcription factors, including the Snail/Slug family, Twist, δEF1/ZEB1, SIP1/ZEB2 and E12/E47 respond to microenvironmental stimuli and function as molecular switches for the EMT program. Snail is a zinc-finger transcriptional repressor controlling EMT during embryogenesis and tumor progression. Through its N-terminal SNAG domain, Snail interacts with several corepressors and epigenetic remodeling complexes to repress specific target genes, such as the E-cadherin gene (CDH1)...
November 2013: Current Cancer Drug Targets
Cheng Chang, Xiaofang Yang, Bryan Pursell, Arthur M Mercurio
The epithelial-mesenchymal transition (EMT) is a fundamental process that underlies development and cancer. Although the EMT involves alterations in the expression of specific integrins that mediate stable adhesion to the basement membrane, such as α6β4, the mechanisms involved are poorly understood. Here, we report that Snai1 inhibits β4 transcription by increasing repressive histone modification (trimethylation of histone H3 at K27 [H3K27Me3]). Surprisingly, Snai1 is expressed and localized in the nucleus in epithelial cells, but it does not repress β4...
October 2013: Molecular and Cellular Biology
C Chiang, K Ayyanathan
Members of the Snail/Gfi-1 domain family of zinc finger proteins are known to recognize the E-box sequence CANNTG, such as that found in the promoter of E-cadherin, however, no studies have shown that the internal "NN" dinucleotides can play a role in different binding affinities. We show via gel shift assays that only the sequences CACCTG and CAGGTG can be recognized more strongly by the SNAG-ZFP members such as Slug, Smuc, Snail, and Scratch while the other combinations of the internal nucleotides were bound weakly...
November 2012: Molekuliarnaia Biologiia
Asif H Chowdhury, Johnny R Ramroop, Ghanshyam Upadhyay, Ananya Sengupta, Anna Andrzejczyk, Shireen Saleque
Gfi1b (growth factor independence 1b) is a zinc finger transcription factor essential for development of the erythroid and megakaryocytic lineages. To elucidate the mechanism underlying Gfi1b function, potential downstream transcriptional targets were identified by chromatin immunoprecipitation and expression profiling approaches. The combination of these approaches revealed the oncogene meis1, which encodes a homeobox protein, as a direct and prominent target of Gfi1b. Examination of the meis1 promoter sequence revealed multiple Gfi1/1b consensus binding motifs...
2013: PloS One
Cindy Chiang, Kasirajan Ayyanathan
The Snail/Gfi-1 (SNAG) family of zinc finger proteins is a group of transcriptional repressors that have been intensively studied in mammals. SNAG family members are similarly structured with an N-terminal SNAG repression domain and a C-terminal zinc finger DNA binding domain, however, the spectrum of target genes they regulate and the ranges of biological functions they govern vary widely between them. They play active roles in transcriptional regulation, formation of repressive chromatin structure, cellular signaling and developmental processes...
April 2013: Cytokine & Growth Factor Reviews
Giovanna Ferrari-Amorotti, Valentina Fragliasso, Roza Esteki, Zelia Prudente, Angela Rachele Soliera, Sara Cattelani, Gloria Manzotti, Giulia Grisendi, Massimo Dominici, Marco Pieraccioli, Giuseppe Raschellà, Claudia Chiodoni, Mario Paolo Colombo, Bruno Calabretta
The process of epithelial-mesenchymal transition (EMT) which is required for cancer cell invasion is regulated by a family of E-box-binding transcription repressors, which include Snail (SNAIL1) and Slug (SNAI2). Snail appears to repress the expression of the EMT marker E-cadherin by epigenetic mechanisms dependent on the interaction of its N-terminal SNAG domain with chromatin-modifying proteins including lysine-specific demethylase 1 (LSD1/KDM1A). We assessed whether blocking Snail/Slug-LSD1 interaction by treatment with Parnate, an enzymatic inhibitor of LSD1, or TAT-SNAG, a cell-permeable peptide corresponding to the SNAG domain of Slug, suppresses the motility and invasiveness of cancer cells of different origin and genetic background...
January 1, 2013: Cancer Research
Patricia Molina-Ortiz, Ana Villarejo, Matthew MacPherson, Vanesa Santos, Amalia Montes, Serhiy Souchelnytskyi, Francisco Portillo, Amparo Cano
Snail1 and Snail2, two highly related members of the Snail superfamily, are direct transcriptional repressors of E-cadherin and EMT inducers. Previous comparative gene profiling analyses have revealed important differences in the gene expression pattern regulated by Snail1 and Snail2, indicating functional differences between both factors. The molecular mechanism of Snail1-mediated repression has been elucidated to some extent, but very little is presently known on the repression mediated by Snail2. In the present work, we report on the characterization of Snail2 repression of E-cadherin and its regulation by phosphorylation...
2012: PloS One
C Dong, Y Wu, Y Wang, C Wang, T Kang, P G Rychahou, Y-I Chi, B M Evers, B P Zhou
Expression of E-cadherin, a hallmark of epithelial-mesenchymal transition (EMT), is often lost due to promoter DNA methylation in basal-like breast cancer (BLBC), which contributes to the metastatic advantage of this disease; however, the underlying mechanism remains unclear. Here, we identified that Snail interacted with Suv39H1 (suppressor of variegation 3-9 homolog 1), a major methyltransferase responsible for H3K9me3 that intimately links to DNA methylation. We demonstrated that the SNAG domain of Snail and the SET domain of Suv39H1 were required for their mutual interactions...
March 14, 2013: Oncogene
Benoît Laurent, Voahangy Randrianarison-Huetz, Emilie Frisan, Charlotte Andrieu-Soler, Eric Soler, Michaela Fontenay, Isabelle Dusanter-Fourt, Dominique Duménil
Gfi-1B is a transcriptional repressor essential for the regulation of erythropoiesis and megakaryopoiesis. Here we identify Gfi-1B p32, a Gfi-1B isoform, as essential for erythroid differentiation. Gfi-1B p32 is generated by alternative splicing and lacks the two first zinc finger domains of the protein. Selective knock down of Gfi-1B p32 compromises erythroid differentiation, whereas its ectopic expression induces erythropoiesis in the absence of erythropoietin. Gfi-1B p32 isoform binds to Gfi-1B target gene promoters and associates with the LSD1-CoREST repressor complex more efficiently than the major Gfi-1B p37 isoform...
February 15, 2012: Journal of Cell Science
Yiwei Lin, Yadi Wu, Junlin Li, Chenfang Dong, Xiaofeng Ye, Young-In Chi, B Mark Evers, Binhua P Zhou
Epithelial-mesenchymal transition (EMT) is a transdifferentiation programme. The mechanism underlying the epigenetic regulation of EMT remains unclear. In this study, we identified that Snail1 interacted with histone lysine-specific demethylase 1 (LSD1). We demonstrated that the SNAG domain of Snail1 and the amine oxidase domain of LSD1 were required for their mutual interaction. Interestingly, the sequence of the SNAG domain is similar to that of the histone H3 tail, and the interaction of Snail1 with LSD1 can be blocked by LSD1 enzymatic inhibitors and a histone H3 peptide...
June 2, 2010: EMBO Journal
Alejandro Barrallo-Gimeno, M Angela Nieto
The Snail transcription factors have crucial roles in metazoan development and disease. A phylogenetic analysis from placozoans to humans confirms that, along with the Scratch genes, Snail genes constitute a subgroup of the C(2)H(2) zinc-finger transcription factors, within which neither the SNAG domain nor the number of fingers define group identities. Independent duplications in the different metazoan groups gave rise to the current complement of Snail genes, and the origin of the Snail/Scratch family can be traced back to a protosnail gene that underwent tandem duplication in the last common ancestor of Diploblasts and Bilateria...
June 2009: Trends in Genetics: TIG
Diego E Montoya-Durango, Chinavenmeni S Velu, Avedis Kazanjian, Meghan E B Rojas, Chris M Jay, Gregory D Longmore, H Leighton Grimes
Growth factor independent-1 (Gfi1) is a zinc finger protein with a SNAG-transcriptional repressor domain. Ajuba is a LIM domain protein that shuttles between the cytoplasm and the nucleus. Ajuba functions as a co-repressor for synthetic Gfi1 SNAG-repressor domain-containing constructs, but a role for Ajuba co-repression of the cognate DNA bound Gfi1 protein has not been defined. Co-immunoprecipitation of synthetic and endogenous proteins and co-elution with gel filtration suggest that an endogenous Ajuba.Gfi1...
November 14, 2008: Journal of Biological Chemistry
Tarik Möröy, Hui Zeng, Jianmin Jin, Kurt Werner Schmid, Alexander Carpinteiro, Erich Gulbins
Gfi1 is a transcriptional repressor with a molecular weight between 47 and 55kDa. The protein has six C-terminal C(2)H(2)-type zinc finger domains and a characteristic stretch of 20 amino acids, called the SNAG-domain, at its N-terminus. Expression of Gfi1 ranges from the hematopoietic and lymphoid system to sensory epithelia, lung and parts of the CNS. Gene knockout studies revealed that Gfi1 is essential for the development of granulocytes and plays a role in macrophage-dependent cytokine production, indicating that this protein shares the responsibility for different lines of defense against pathogens...
2008: Immunobiology
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