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1.
J Biol Chem ; 289(2): 868-84, 2014 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-24235145

RESUMEN

The mixed lineage leukemia-1 (MLL1) core complex predominantly catalyzes mono- and dimethylation of histone H3 at lysine 4 (H3K4) and is frequently altered in aggressive acute leukemias. The molecular mechanisms that account for conversion of mono- to dimethyl H3K4 (H3K4me1,2) are not well understood. In this investigation, we report that the suppressor of variegation, enhancer of zeste, trithorax (SET) domains from human MLL1 and Drosophila Trithorax undergo robust intramolecular automethylation reactions at an evolutionarily conserved cysteine residue in the active site, which is inhibited by unmodified histone H3. The location of the automethylation in the SET-I subdomain indicates that the MLL1 SET domain possesses significantly more conformational plasticity in solution than suggested by its crystal structure. We also report that MLL1 methylates Ash2L in the absence of histone H3, but only when assembled within a complex with WDR5 and RbBP5, suggesting a restraint for the architectural arrangement of subunits within the complex. Using MLL1 and Ash2L automethylation reactions as probes for histone binding, we observed that both automethylation reactions are significantly inhibited by stoichiometric amounts of unmethylated histone H3, but not by histones previously mono-, di-, or trimethylated at H3K4. These results suggest that the H3K4me1 intermediate does not significantly bind to the MLL1 SET domain during the dimethylation reaction. Consistent with this hypothesis, we demonstrate that the MLL1 core complex assembled with a catalytically inactive SET domain variant preferentially catalyzes H3K4 dimethylation using the H3K4me1 substrate. Taken together, these results are consistent with a "two-active site" model for multiple H3K4 methylation by the MLL1 core complex.


Asunto(s)
Histonas/metabolismo , Lisina/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Sustitución de Aminoácidos , Animales , Sitios de Unión/genética , Cisteína/química , Cisteína/genética , Cisteína/metabolismo , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Electroforesis en Gel de Poliacrilamida , N-Metiltransferasa de Histona-Lisina/química , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/química , Humanos , Péptidos y Proteínas de Señalización Intracelular , Cinética , Lisina/química , Espectrometría de Masas/métodos , Metilación , Modelos Moleculares , Mutación , Proteína de la Leucemia Mieloide-Linfoide/química , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Estructura Terciaria de Proteína , Factores de Transcripción/química , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
2.
Glia ; 63(9): 1568-80, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25880604

RESUMEN

Astrocytes produce and export the antioxidant glutathione (GSH). Previously, we found that interleukin-1ß (IL-1ß) enhanced the expression of astrocyte system xc (-) , the transporter that delivers the rate-limiting substrate for GSH synthesis-cyst(e)ine. Herein, we demonstrate directly that IL-1ß mediates a time-dependent increase in extracellular GSH levels in cortical astrocyte cultures, suggesting both enhanced synthesis and export. This increased GSH production was blocked by inhibition of nuclear factor-κB (NF-κB) activity but not by inhibition of p38 MAPK. To determine whether this increase could provide protection against oxidative stress, the oxidants tert-butyl hydroperoxide (tBOOH) and ferrous sulfate (FeSO4 ) were employed. IL-1ß treatment prevented the increase in reactive oxygen species produced in astrocytes following tBOOH exposure. Additionally, the toxicity induced by tBOOH or FeSO4 exposure was significantly attenuated following treatment with IL-1ß, an effect reversed by concomitant exposure to l-buthionine-S,R-sulfoximine (BSO), which prevented the IL-1ß-mediated rise in GSH production. IL-1ß failed to increase GSH or to provide protection against t-BOOH toxicity in astrocyte cultures derived from IL-1R1 null mutant mice. Overall, our data indicate that under certain conditions IL-1ß may be an important stimulus for increasing astrocyte GSH production, and potentially, total antioxidant capacity in brain, via an NF-κB-dependent process.


Asunto(s)
Astrocitos/metabolismo , Glutatión/metabolismo , Interleucina-1beta/metabolismo , FN-kappa B/metabolismo , Oxidantes/toxicidad , Animales , Astrocitos/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Corteza Cerebral/metabolismo , Interleucina-1beta/administración & dosificación , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
3.
Development ; 138(11): 2223-34, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21558371

RESUMEN

The C. elegans germline provides an excellent model for analyzing the regulation of stem cell activity and the decision to differentiate and undergo meiotic development. The distal end of the adult hermaphrodite germline contains the proliferative zone, which includes a population of mitotically cycling cells and cells in meiotic S phase, followed by entry into meiotic prophase. The proliferative fate is specified by somatic distal tip cell (DTC) niche-germline GLP-1 Notch signaling through repression of the redundant GLD-1 and GLD-2 pathways that promote entry into meiosis. Here, we describe characteristics of the proliferative zone, including cell cycle kinetics and population dynamics, as well as the role of specific cell cycle factors in both cell cycle progression and the decision between the proliferative and meiotic cell fate. Mitotic cell cycle progression occurs rapidly, continuously, with little or no time spent in G1, and with cyclin E (CYE-1) levels and activity high throughout the cell cycle. In addition to driving mitotic cell cycle progression, CYE-1 and CDK-2 also play an important role in proliferative fate specification. Genetic analysis indicates that CYE-1/CDK-2 promotes the proliferative fate downstream or in parallel to the GLD-1 and GLD-2 pathways, and is important under conditions of reduced GLP-1 signaling, possibly corresponding to mitotically cycling proliferative zone cells that are displaced from the DTC niche. Furthermore, we find that GLP-1 signaling regulates a third pathway, in addition to the GLD-1 and GLD-2 pathways and also independent of CYE-1/CDK-2, to promote the proliferative fate/inhibit meiotic entry.


Asunto(s)
Caenorhabditis elegans/citología , Ciclo Celular/fisiología , Ciclina E/metabolismo , Quinasa 2 Dependiente de la Ciclina/metabolismo , Células Germinativas/citología , Meiosis/fisiología , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiología , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Ciclina E/genética , Quinasa 2 Dependiente de la Ciclina/genética , Silenciador del Gen , Células Germinativas/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Polinucleotido Adenililtransferasa/metabolismo , ARN Interferente Pequeño , Receptores Notch , Células Madre
4.
J Biol Chem ; 286(5): 3359-69, 2011 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-21106533

RESUMEN

Gene expression within the context of eukaryotic chromatin is regulated by enzymes that catalyze histone lysine methylation. Histone lysine methyltransferases that have been identified to date possess the evolutionarily conserved SET or Dot1-like domains. We previously reported the identification of a new multi-subunit histone H3 lysine 4 methyltransferase lacking homology to the SET or Dot1 family of histone lysine methyltransferases. This enzymatic activity requires a complex that includes WRAD (WDR5, RbBP5, Ash2L, and DPY-30), a complex that is part of the MLL1 (mixed lineage leukemia protein-1) core complex but that also exists independently of MLL1 in the cell. Here, we report that the minimal complex required for WRAD enzymatic activity includes WDR5, RbBP5, and Ash2L and that DPY-30, although not required for enzymatic activity, increases the histone substrate specificity of the WRAD complex. We also show that WRAD requires zinc for catalytic activity, displays Michaelis-Menten kinetics, and is inhibited by S-adenosyl-homocysteine. In addition, we demonstrate that WRAD preferentially methylates lysine 4 of histone H3 within the context of the H3/H4 tetramer but does not methylate nucleosomal histone H3 on its own. In contrast, we find that MLL1 and WRAD are required for nucleosomal histone H3 methylation, and we provide evidence suggesting that each plays distinct structural and catalytic roles in the recognition and methylation of a nucleosome substrate. Our results indicate that WRAD is a new H3K4 methyltransferase with functions that include regulating the substrate and product specificities of the MLL1 core complex.


Asunto(s)
N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Catálisis , Humanos , Cinética , Metilación , Complejos Multiproteicos , Especificidad por Sustrato , Zinc
5.
J Biol Chem ; 286(16): 14352-61, 2011 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-21349835

RESUMEN

Myosin-Va (Myo5a) is a motor protein associated with synaptic vesicles (SVs) but the mechanism by which it interacts has not yet been identified. A potential class of binding partners are Rab GTPases and Rab3A is known to associate with SVs and is involved in SV trafficking. We performed experiments to determine whether Rab3A interacts with Myo5a and whether it is required for transport of neuronal vesicles. In vitro motility assays performed with axoplasm from the squid giant axon showed a requirement for a Rab GTPase in Myo5a-dependent vesicle transport. Furthermore, mouse recombinant Myo5a tail revealed that it associated with Rab3A in rat brain synaptosomal preparations in vitro and the association was confirmed by immunofluorescence imaging of primary neurons isolated from the frontal cortex of mouse brains. Synaptosomal Rab3A was retained on recombinant GST-tagged Myo5a tail affinity columns in a GTP-dependent manner. Finally, the direct interaction of Myo5a and Rab3A was determined by sedimentation velocity analytical ultracentrifugation using recombinant mouse Myo5a tail and human Rab3A. When both proteins were incubated in the presence of 1 mm GTPγS, Myo5a tail and Rab3A formed a complex and a direct interaction was observed. Further analysis revealed that GTP-bound Rab3A interacts with both the monomeric and dimeric species of the Myo5a tail. However, the interaction between Myo5a tail and nucleotide-free Rab3A did not occur. Thus, our results show that Myo5a and Rab3A are direct binding partners and interact on SVs and that the Myo5a/Rab3A complex is involved in transport of neuronal vesicles.


Asunto(s)
Cadenas Pesadas de Miosina/química , Miosina Tipo V/química , Neuronas/metabolismo , Proteína de Unión al GTP rab3A/química , Animales , Encéfalo/metabolismo , Decapodiformes , Dimerización , Lóbulo Frontal/metabolismo , Guanosina Trifosfato/química , Humanos , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/química
6.
Curr Biol ; 15(21): 1972-8, 2005 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-16271877

RESUMEN

During meiosis in C. elegans, unpaired chromosomes and chromosomal regions accumulate high levels of histone H3 lysine 9 dimethylation (H3K9me2), a modification associated with facultative heterochromatin assembly and the resulting transcriptional silencing. Meiotic silencing of unpaired DNA may be a widely conserved genome defense mechanism. The mechanisms of meiotic silencing remain unclear, although both transcriptional and posttranscriptional processes are implicated. Cellular RNA-dependent RNA polymerases (RdRPs) function in development and RNA-mediated silencing in many species and in heterochromatin assembly in S. pombe. There are four C. elegans RdRPs, including two with known germline functions. EGO-1 is required for fertility and robust germline RNAi. RRF-3 acts genetically to repress RNAi and is required for normal meiosis and spermatogenesis at elevated temperatures (S. L'Hernault, personal communication). Among C. elegans RdRPs, we find that only EGO-1 is required for H3K9me2 enrichment on unpaired chromosomal regions during meiosis. This H3K9me2 enrichment does not require Dicer or Drosha nuclease or any of several other proteins required for RNAi. ego-1 interacts genetically with him-17, another regulator of chromatin and meiosis, to promote germline development. We conclude that EGO-1 is an essential component of meiotic silencing in C. elegans.


Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/enzimología , ADN/metabolismo , Silenciador del Gen/fisiología , Heterocromatina/fisiología , Meiosis/fisiología , ARN Polimerasa Dependiente del ARN/metabolismo , Animales , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/fisiología , Proteínas de Ciclo Celular/metabolismo , Técnica del Anticuerpo Fluorescente Indirecta , Heterocromatina/enzimología , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina/metabolismo , Meiosis/genética , Metilación , Modelos Moleculares , Mutación/genética , Proteína Metiltransferasas , ARN Polimerasa Dependiente del ARN/genética , ARN Polimerasa Dependiente del ARN/fisiología
7.
Genetics ; 170(3): 1121-32, 2005 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15911573

RESUMEN

Caenorhabditis elegans EGO-1, a putative cellular RNA-directed RNA polymerase, promotes several aspects of germline development, including proliferation, meiosis, and gametogenesis, and ensures a robust response to RNA interference. In C. elegans, GLP-1/Notch signaling from the somatic gonad maintains a population of proliferating germ cells, while entry of germ cells into meiosis is triggered by the GLD-1 and GLD-2 pathways. GLP-1 signaling prevents germ cells from entering meiosis by inhibiting GLD-1 and GLD-2 activity. We originally identified the ego-1 gene on the basis of a genetic interaction with glp-1. Here, we investigate the role of ego-1 in germline proliferation. Our data indicate that EGO-1 does not positively regulate GLP-1 protein levels or GLP-1 signaling activity. Moreover, GLP-1 signaling does not positively regulate EGO-1 activity. EGO-1 does not inhibit expression of GLD-1 protein in the distal germline. Instead, EGO-1 acts in parallel with GLP-1 signaling to influence the proliferation vs. meiosis fate choice. Moreover, EGO-1 and GLD-1 act in parallel to ensure germline health. Finally, the size and distribution of nuclear pore complexes and perinuclear P granules are altered in the absence of EGO-1, effects that disrupt germ cell biology per se and probably limit germline growth.


Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/enzimología , Células Germinativas/metabolismo , Poro Nuclear/metabolismo , ARN Polimerasa Dependiente del ARN/metabolismo , Transducción de Señal/fisiología , Animales , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proliferación Celular , Gránulos Citoplasmáticos/metabolismo , Electroforesis en Gel de Poliacrilamida , Técnica del Anticuerpo Fluorescente Indirecta , Células Germinativas/citología , Células Germinativas/fisiología , Glicoproteínas de Membrana/metabolismo , ARN Polimerasa Dependiente del ARN/genética , Receptores Notch/metabolismo , Transducción de Señal/genética
8.
Genetics ; 168(2): 817-30, 2004 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15514056

RESUMEN

In the Caenorhabditis elegans germline, proliferation is induced by Notch-type signaling. Entry of germ cells into meiosis is triggered by activity of the GLD-1 and GLD-2 pathways, which function redundantly to promote meiosis and/or inhibit proliferation. Activation of the germline Notch-type receptor, GLP-1, ultimately inhibits the activities of the GLD-1 and GLD-2 pathways. We previously identified several ego (enhancer of glp-1) genes that promote germline proliferation and interact genetically with the GLP-1 signaling pathway. Here, we show that atx-2 is an ego gene. Our data suggest that ATX-2 is not a positive regulator of the GLP-1 signaling pathway and GLP-1 signaling is not the sole positive regulator of ATX-2 activity. Moreover, our data indicate that GLP-1 must have an additional function, which may be to repress activity of a third meiotic entry pathway that would work in parallel with the GLD-1 and GLD-2 pathways. In addition to its role in proliferation, ATX-2 acts downstream of FOG-2 to promote the female germline fate.


Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiología , Proliferación Celular , Meiosis/fisiología , Glicoproteínas de Membrana/metabolismo , Oocitos/fisiología , Proteínas/metabolismo , Secuencia de Aminoácidos , Animales , Repetición de Anquirina , Ataxinas , Femenino , Células Germinativas , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso , Polinucleotido Adenililtransferasa/metabolismo , Proteínas/antagonistas & inhibidores , Proteínas/genética , Interferencia de ARN , Receptores Notch , Homología de Secuencia de Aminoácido , Transducción de Señal
9.
J Mol Biol ; 426(12): 2283-99, 2014 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-24680668

RESUMEN

The mixed lineage leukemia-1 (MLL1) enzyme is a histone H3 lysine 4 (H3K4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human SET1 family of enzymes that include MLL1-MLL4 and SETd1a,b. Dimethylation of H3K4 requires a sub-complex including WRAD (WDR5, RbBP5, Ash2L, and DPY-30), which binds to each SET1 family member forming a minimal core complex that is required for multiple lysine methylation. We recently demonstrated that WRAD is a novel histone methyltransferase that preferentially catalyzes H3K4 dimethylation in a manner that is dependent on an unknown non-active-site surface from the MLL1 SET domain. Recent genome sequencing studies have identified a number of human disease-associated missense mutations that localize to the SET domains of several MLL family members. In this investigation, we mapped many of these mutations onto the three-dimensional structure of the SET domain and noticed that a subset of MLL2 (KMT2D, ALR, MLL4)-associated Kabuki syndrome missense mutations map to a common solvent-exposed surface that is not expected to alter enzymatic activity. We introduced these mutations into the MLL1 SET domain and observed that all are defective for H3K4 dimethylation by the MLL1 core complex, which is associated with a loss of the ability of MLL1 to interact with WRAD or with the RbBP5/Ash2L heterodimer. Our results suggest that amino acids from this surface, which we term the Kabuki interaction surface or KIS, are required for formation of a second active site within SET1 family core complexes.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proteínas Nucleares/metabolismo , Dominios y Motivos de Interacción de Proteínas , Factores de Transcripción/metabolismo , Secuencia de Aminoácidos , Dominio Catalítico , N-Metiltransferasa de Histona-Lisina , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación Missense , Proteína de la Leucemia Mieloide-Linfoide/química , Proteína de la Leucemia Mieloide-Linfoide/genética , Unión Proteica , Conformación Proteica , Mapeo de Interacción de Proteínas
10.
J Biol Chem ; 284(36): 24242-56, 2009 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-19556245

RESUMEN

Transcription in eukaryotic genomes depends on enzymes that regulate the degree of histone H3 lysine 4 (H3K4) methylation. The mixed lineage leukemia protein-1 (MLL1) is a member of the SET1 family of H3K4 methyltransferases and is frequently rearranged in acute leukemias. Despite sequence comparisons that predict that SET1 family enzymes should only monomethylate their substrates, mono-, di-, and trimethylation of H3K4 has been attributed to SET1 family complexes in vivo and in vitro. To better understand this paradox, we have biochemically reconstituted and characterized a five-component 200-kDa MLL1 core complex containing human MLL1, WDR5, RbBP5, Ash2L, and DPY-30. We demonstrate that the isolated MLL1 SET domain is a slow monomethyltransferase and that tyrosine 3942 of MLL1 prevents di- and trimethylation of H3K4. In contrast, a complex containing the MLL1 SET domain, WDR5, RbBP5, Ash2L, and DPY-30, displays a marked approximately 600-fold increase in enzymatic activity but only to the dimethyl form of H3K4. Single turnover kinetic experiments reveal that the reaction leading to H3K4 dimethylation involves the transient accumulation of a monomethylated species, suggesting that the MLL1 core complex uses a non-processive mechanism to catalyze multiple lysine methylation. We have also discovered that the non-SET domain components of the MLL1 core complex possess a previously unrecognized methyltransferase activity that catalyzes H3K4 dimethylation within the MLL1 core complex. Our results suggest that the mechanism of multiple lysine methylation by the MLL1 core complex involves the sequential addition of two methyl groups at two distinct active sites within the complex.


Asunto(s)
Lisina/metabolismo , Complejos Multiproteicos/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Reordenamiento Génico/genética , N-Metiltransferasa de Histona-Lisina/química , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/química , Histonas/genética , Histonas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Leucemia/genética , Leucemia/metabolismo , Lisina/genética , Metilación , Complejos Multiproteicos/química , Complejos Multiproteicos/genética , Proteína de la Leucemia Mieloide-Linfoide/química , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Celulares de Unión al Retinol/química , Proteínas Celulares de Unión al Retinol/genética , Proteínas Celulares de Unión al Retinol/metabolismo , Factores de Transcripción/química , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
11.
J Biol Chem ; 283(47): 32162-75, 2008 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-18829457

RESUMEN

The mixed lineage leukemia protein-1 (MLL1) belongs to the SET1 family of histone H3 lysine 4 methyltransferases. Recent studies indicate that the catalytic subunits of SET1 family members are regulated by interaction with a conserved core group of proteins that include the WD repeat protein-5 (WDR5), retinoblastoma-binding protein-5 (RbBP5), and the absent small homeotic-2-like protein (Ash2L). It has been suggested that WDR5 functions to bridge the interactions between the catalytic and regulatory subunits of SET1 family complexes. However, the molecular details of these interactions are unknown. To gain insight into the interactions among these proteins, we have determined the biophysical basis for the interaction between the human WDR5 and MLL1. Our studies reveal that WDR5 preferentially recognizes a previously unidentified and conserved arginine-containing motif, called the "Win" or WDR5 interaction motif, which is located in the N-SET region of MLL1 and other SET1 family members. Surprisingly, our structural and functional studies show that WDR5 recognizes arginine 3765 of the MLL1 Win motif using the same arginine binding pocket on WDR5 that was previously shown to bind histone H3. We demonstrate that WDR5's recognition of arginine 3765 of MLL1 is essential for the assembly and enzymatic activity of the MLL1 core complex in vitro.


Asunto(s)
Arginina/química , Proteína de la Leucemia Mieloide-Linfoide/química , Secuencias de Aminoácidos , Secuencia de Aminoácidos , ADN Complementario/metabolismo , Proteínas de Unión al ADN/química , N-Metiltransferasa de Histona-Lisina/química , Humanos , Péptidos y Proteínas de Señalización Intracelular , Lisina/química , Datos de Secuencia Molecular , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proteínas Nucleares/química , Unión Proteica , Estructura Terciaria de Proteína , Homología de Secuencia de Aminoácido , Bazo/metabolismo , Factores de Transcripción/química
12.
Genesis ; 44(9): 412-8, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16937415

RESUMEN

In C. elegans, a population of proliferating germ cells is maintained via GLP-1/Notch signaling; in the absence of GLP-1 signaling, germ cells prematurely enter meiosis and differentiate. We previously identified ego (enhancer of glp-1) genes that promote germline proliferation and interact genetically with the GLP-1 signaling pathway. Here, we report that iffb-1 (initiation factor five B) is an ego gene. iffb-1 encodes the sole C. elegans isoform of eukaryotic translation initiation factor 5B, a protein essential for translation. We have used RNA interference and a deletion mutation to determine the developmental consequences of reduced iffb-1 activity. Our data indicate that maternal iffb-1 gene expression is sufficient for embryogenesis, and zygotic iffb-1 expression is required for development beyond late L1/early L2 stage. Partial reduction in iffb-1 expression delays larval development and can severely disrupt proliferation and differentiation of germ cells. We hypothesize that germline development is particularly sensitive to iffb-1 expression level.


Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/crecimiento & desarrollo , Factores Eucarióticos de Iniciación/metabolismo , Regulación del Desarrollo de la Expresión Génica , Células Germinativas/metabolismo , Regiones no Traducidas 3' , Regiones no Traducidas 5' , Animales , Secuencia de Bases , Caenorhabditis elegans/citología , Caenorhabditis elegans/embriología , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Codón , Embrión no Mamífero , Exones , Eliminación de Gen , Genes de Helminto , Células Germinativas/citología , Células Germinativas/fisiología , Larva/crecimiento & desarrollo , Estadios del Ciclo de Vida , Glicoproteínas de Membrana/metabolismo , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , Estructura Terciaria de Proteína , Interferencia de ARN , Receptores Notch/metabolismo , Homología de Secuencia de Ácido Nucleico
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