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1.
Mol Cell ; 84(11): 2070-2086.e20, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38703770

RESUMEN

The MYCN oncoprotein binds active promoters in a heterodimer with its partner protein MAX. MYCN also interacts with the nuclear exosome, a 3'-5' exoribonuclease complex, suggesting a function in RNA metabolism. Here, we show that MYCN forms stable high-molecular-weight complexes with the exosome and multiple RNA-binding proteins. MYCN binds RNA in vitro and in cells via a conserved sequence termed MYCBoxI. In cells, MYCN associates with thousands of intronic transcripts together with the ZCCHC8 subunit of the nuclear exosome targeting complex and enhances their processing. Perturbing exosome function results in global re-localization of MYCN from promoters to intronic RNAs. On chromatin, MYCN is then replaced by the MNT(MXD6) repressor protein, inhibiting MYCN-dependent transcription. RNA-binding-deficient alleles show that RNA-binding limits MYCN's ability to activate cell growth-related genes but is required for MYCN's ability to promote progression through S phase and enhance the stress resilience of neuroblastoma cells.


Asunto(s)
Proteína Proto-Oncogénica N-Myc , Proteínas Nucleares , Proteínas Oncogénicas , Proteínas de Unión al ARN , Proteína Proto-Oncogénica N-Myc/metabolismo , Proteína Proto-Oncogénica N-Myc/genética , Humanos , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Proteínas Oncogénicas/metabolismo , Proteínas Oncogénicas/genética , Regiones Promotoras Genéticas , Línea Celular Tumoral , Neuroblastoma/metabolismo , Neuroblastoma/genética , Neuroblastoma/patología , Exosomas/metabolismo , Exosomas/genética , Intrones , Unión Proteica , Núcleo Celular/metabolismo , Complejo Multienzimático de Ribonucleasas del Exosoma/metabolismo , Complejo Multienzimático de Ribonucleasas del Exosoma/genética , Regulación Neoplásica de la Expresión Génica , ARN/metabolismo , ARN/genética , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Proliferación Celular
2.
Mol Cell ; 81(4): 830-844.e13, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33453168

RESUMEN

The MYC oncoprotein globally affects the function of RNA polymerase II (RNAPII). The ability of MYC to promote transcription elongation depends on its ubiquitylation. Here, we show that MYC and PAF1c (polymerase II-associated factor 1 complex) interact directly and mutually enhance each other's association with active promoters. PAF1c is rapidly transferred from MYC onto RNAPII. This transfer is driven by the HUWE1 ubiquitin ligase and is required for MYC-dependent transcription elongation. MYC and HUWE1 promote histone H2B ubiquitylation, which alters chromatin structure both for transcription elongation and double-strand break repair. Consistently, MYC suppresses double-strand break accumulation in active genes in a strictly PAF1c-dependent manner. Depletion of PAF1c causes transcription-dependent accumulation of double-strand breaks, despite widespread repair-associated DNA synthesis. Our data show that the transfer of PAF1c from MYC onto RNAPII efficiently couples transcription elongation with double-strand break repair to maintain the genomic integrity of MYC-driven tumor cells.


Asunto(s)
Roturas del ADN de Doble Cadena , Reparación del ADN , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-myc/metabolismo , Elongación de la Transcripción Genética , ATPasas Asociadas con Actividades Celulares Diversas/genética , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Línea Celular Tumoral , Histonas/genética , Histonas/metabolismo , Humanos , Proteínas Proto-Oncogénicas c-myc/genética , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación
3.
Mol Cell ; 74(4): 674-687.e11, 2019 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-30928206

RESUMEN

The MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and enhances RNA polymerase II (Pol II) function, but its precise mode of action is poorly understood. Using mass spectrometry of both MYC and Pol II complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF. MYC directly binds SPT5, recruits SPT5 to promoters, and enables the CDK7-dependent transfer of SPT5 onto Pol II. Consistent with known functions of SPT5, MYC is required for fast and processive transcription elongation. Intriguingly, the high levels of MYC that are expressed in tumors sequester SPT5 into non-functional complexes, thereby decreasing the expression of growth-suppressive genes. Altogether, these results argue that MYC controls the productive assembly of processive Pol II elongation complexes and provide insight into how oncogenic levels of MYC permit uncontrolled cellular growth.


Asunto(s)
Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas c-myc/genética , ARN Polimerasa II/genética , Transcripción Genética , Factores de Elongación Transcripcional/genética , Línea Celular Tumoral , Proliferación Celular/genética , Quinasas Ciclina-Dependientes/genética , Chaperonas de Histonas/genética , Humanos , Neoplasias/genética , Regiones Promotoras Genéticas , Quinasa Activadora de Quinasas Ciclina-Dependientes
4.
Nucleic Acids Res ; 52(6): 3050-3068, 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38224452

RESUMEN

RNA-binding proteins emerge as effectors of the DNA damage response (DDR). The multifunctional non-POU domain-containing octamer-binding protein NONO/p54nrb marks nuclear paraspeckles in unperturbed cells, but also undergoes re-localization to the nucleolus upon induction of DNA double-strand breaks (DSBs). However, NONO nucleolar re-localization is poorly understood. Here we show that the topoisomerase II inhibitor etoposide stimulates the production of RNA polymerase II-dependent, DNA damage-inducible antisense intergenic non-coding RNA (asincRNA) in human cancer cells. Such transcripts originate from distinct nucleolar intergenic spacer regions and form DNA-RNA hybrids to tether NONO to the nucleolus in an RNA recognition motif 1 domain-dependent manner. NONO occupancy at protein-coding gene promoters is reduced by etoposide, which attenuates pre-mRNA synthesis, enhances NONO binding to pre-mRNA transcripts and is accompanied by nucleolar detention of a subset of such transcripts. The depletion or mutation of NONO interferes with detention and prolongs DSB signalling. Together, we describe a nucleolar DDR pathway that shields NONO and aberrant transcripts from DSBs to promote DNA repair.


Asunto(s)
Roturas del ADN de Doble Cadena , Proteínas de Unión al ADN , Humanos , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Etopósido/farmacología , Precursores del ARN/metabolismo , Factores de Transcripción/metabolismo , ADN , Proteínas de Unión al ARN/metabolismo
5.
Proc Natl Acad Sci U S A ; 114(44): E9224-E9232, 2017 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-29078288

RESUMEN

The Myc oncogene is a transcription factor with a powerful grip on cellular growth and proliferation. The physical interaction of Myc with the E-box DNA motif has been extensively characterized, but it is less clear whether this sequence-specific interaction is sufficient for Myc's binding to its transcriptional targets. Here we identify the PAF1 complex, and specifically its component Leo1, as a factor that helps recruit Myc to target genes. Since the PAF1 complex is typically associated with active genes, this interaction with Leo1 contributes to Myc targeting to open promoters.


Asunto(s)
Proteínas de Drosophila/genética , Drosophila/genética , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-myc/genética , Factores de Transcripción/genética , Animales , Células Cultivadas , Transcripción Genética/genética
6.
Nat Genet ; 40(9): 1084-91, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19165923

RESUMEN

Myc proteins are powerful proto-oncoproteins and important promoters of growth and proliferation during normal development. They are thought to exercise their effects upon binding to their partner protein Max, and their activities are largely antagonized by complexes of Max with Mnt or an Mxd family protein. Although the biological functions of Myc, Mxd and Mnt have been intensively studied, comparatively little is known about the in vivo role of Max. Here we generate Max loss-of-function and reduction-of-function mutations in Drosophila melanogaster to address the contribution of Max to Myc-dependent growth control. We find that many biological activities of Myc do not, or only partly, require the association with Max--for example, the control of endoreplication and cell competition-and that a Myc mutant that does not interact with Max retains substantial biological activity. We further show that Myc can control RNA polymerase III independently of Max, which explains some of Myc's observed biological activities. These studies show the ability of Myc to function independently of Max in vivo and thus change the current model of Max network function.


Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/fisiología , Proteínas de Drosophila/fisiología , Drosophila melanogaster/genética , Proteínas Proto-Oncogénicas c-myc/fisiología , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Proteínas de Drosophila/genética , Regulación Neoplásica de la Expresión Génica , Metamorfosis Biológica , Fenotipo , ARN Polimerasa III/metabolismo , Proteínas Represoras/fisiología , Transgenes , Alas de Animales
7.
BMC Biol ; 13: 25, 2015 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-25888729

RESUMEN

BACKGROUND: Myc proteins are essential regulators of animal growth during normal development, and their deregulation is one of the main driving factors of human malignancies. They function as transcription factors that (in vertebrates) control many growth- and proliferation-associated genes, and in some contexts contribute to global gene regulation. RESULTS: We combine chromatin immunoprecipitation-sequencing (ChIPseq) and RNAseq approaches in Drosophila tissue culture cells to identify a core set of less than 500 Myc target genes, whose salient function resides in the control of ribosome biogenesis. Among these genes we find the non-coding snoRNA genes as a large novel class of Myc targets. All assayed snoRNAs are affected by Myc, and many of them are subject to direct transcriptional activation by Myc, both in Drosophila and in vertebrates. The loss of snoRNAs impairs growth during normal development, whereas their overexpression increases tumor mass in a model for neuronal tumors. CONCLUSIONS: This work shows that Myc acts as a master regulator of snoRNP biogenesis. In addition, in combination with recent observations of snoRNA involvement in human cancer, it raises the possibility that Myc's transforming effects are partially mediated by this class of non-coding transcripts.


Asunto(s)
Drosophila melanogaster/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Nucleolar Pequeño/metabolismo , Animales , Sitios de Unión/genética , Línea Celular Tumoral , Drosophila melanogaster/crecimiento & desarrollo , Regulación del Desarrollo de la Expresión Génica , Genes de Insecto , Humanos , Modelos Biológicos , Regiones Promotoras Genéticas/genética , Unión Proteica/genética , ARN Nucleolar Pequeño/genética , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Ribosomas/metabolismo , Vertebrados/genética
8.
Life Sci Alliance ; 7(1)2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37935464

RESUMEN

The transcription factor SPT5 physically interacts with MYC oncoproteins and is essential for efficient transcriptional activation of MYC targets in cultured cells. Here, we use Drosophila to address the relevance of this interaction in a living organism. Spt5 displays moderate synergy with Myc in fast proliferating young imaginal disc cells. During later development, Spt5-knockdown has no detectable consequences on its own, but strongly enhances eye defects caused by Myc overexpression. Similarly, Spt5-knockdown in larval type 2 neuroblasts has only mild effects on brain development and survival of control flies, but dramatically shrinks the volumes of experimentally induced neuroblast tumors and significantly extends the lifespan of tumor-bearing animals. This beneficial effect is still observed when Spt5 is knocked down systemically and after tumor initiation, highlighting SPT5 as a potential drug target in human oncology.


Asunto(s)
Neoplasias Encefálicas , Drosophila , Animales , Humanos , Encéfalo/metabolismo , Neoplasias Encefálicas/genética , Drosophila/genética , Drosophila/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factores de Elongación Transcripcional/metabolismo
9.
Nat Commun ; 15(1): 1446, 2024 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-38365788

RESUMEN

In pancreatic ductal adenocarcinoma (PDAC), endogenous MYC is required for S-phase progression and escape from immune surveillance. Here we show that MYC in PDAC cells is needed for the recruitment of the PAF1c transcription elongation complex to RNA polymerase and that depletion of CTR9, a PAF1c subunit, enables long-term survival of PDAC-bearing mice. PAF1c is largely dispensable for normal proliferation and regulation of MYC target genes. Instead, PAF1c limits DNA damage associated with S-phase progression by being essential for the expression of long genes involved in replication and DNA repair. Surprisingly, the survival benefit conferred by CTR9 depletion is not due to DNA damage, but to T-cell activation and restoration of immune surveillance. This is because CTR9 depletion releases RNA polymerase and elongation factors from the body of long genes and promotes the transcription of short genes, including MHC class I genes. The data argue that functionally distinct gene sets compete for elongation factors and directly link MYC-driven S-phase progression to tumor immune evasion.


Asunto(s)
Fenómenos Bioquímicos , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas c-myc , Animales , Ratones , Carcinoma Ductal Pancreático/patología , Proliferación Celular , ARN Polimerasas Dirigidas por ADN/metabolismo , Evasión Inmune , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas c-myc/metabolismo
10.
J Biol Chem ; 285(51): 39623-36, 2010 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-20937797

RESUMEN

The Myc proto-oncoproteins are transcription factors that recognize numerous target genes through hexameric DNA sequences called E-boxes. The mechanism by which they then activate the expression of these targets is still under debate. Here, we use an RNAi screen in Drosophila S2 cells to identify Drosophila host cell factor (dHCF) as a novel co-factor for Myc that is functionally required for the activation of a Myc-dependent reporter construct. dHCF is also essential for the full activation of endogenous Myc target genes in S2 cells, and for the ability of Myc to promote growth in vivo. Myc and dHCF physically interact, and they colocalize on common target genes. Furthermore, down-regulation of dHCF-associated histone acetyltransferase and histone methyltransferase complexes in vivo interferes with the Myc biological activities. We therefore propose that dHCF recruits such chromatin-modifying complexes and thereby contributes to the expression of Myc targets and hence to the execution of Myc biological activities.


Asunto(s)
Proliferación Celular , Cromatina/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/metabolismo , Regulación de la Expresión Génica/fisiología , Factores de Transcripción/metabolismo , Transcripción Genética/fisiología , Animales , Línea Celular , Cromatina/genética , Proteínas de Unión al ADN/inmunología , Proteínas de Drosophila/genética , Proteínas de Drosophila/inmunología , Drosophila melanogaster , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Complejos Multienzimáticos/genética , Complejos Multienzimáticos/metabolismo , Factores de Transcripción/inmunología
11.
Cancer Res ; 81(16): 4242-4256, 2021 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-34145038

RESUMEN

Deregulated expression of the MYC oncoprotein enables tumor cells to evade immune surveillance, but the mechanisms underlying this surveillance are poorly understood. We show here that endogenous MYC protects pancreatic ductal adenocarcinoma (PDAC) driven by KRASG12D and TP53R172H from eradication by the immune system. Deletion of TANK-binding kinase 1 (TBK1) bypassed the requirement for high MYC expression. TBK1 was active due to the accumulation of double-stranded RNA (dsRNA), which was derived from inverted repetitive elements localized in introns of nuclear genes. Nuclear-derived dsRNA is packaged into extracellular vesicles and subsequently recognized by toll-like receptor 3 (TLR3) to activate TBK1 and downstream MHC class I expression in an autocrine or paracrine manner before being degraded in lysosomes. MYC suppressed loading of dsRNA onto TLR3 and its subsequent degradation via association with MIZ1. Collectively, these findings suggest that MYC and MIZ1 suppress a surveillance pathway that signals perturbances in mRNA processing to the immune system, which facilitates immune evasion in PDAC. SIGNIFICANCE: This study identifies a TBK1-dependent pathway that links dsRNA metabolism to antitumor immunity and shows that suppression of TBK1 is a critical function of MYC in pancreatic ductal adenocarcinoma.


Asunto(s)
Adenocarcinoma/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Evasión Inmune , Factores de Transcripción de Tipo Kruppel/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Bicatenario , Adenocarcinoma/inmunología , Animales , Transporte Biológico , Carcinoma Ductal Pancreático/inmunología , Núcleo Celular/metabolismo , Eliminación de Gen , Células HEK293 , Humanos , Sistema Inmunológico , Intrones , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Desnudos , Neoplasias Pancreáticas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Análisis de Secuencia de ADN , Proteína p53 Supresora de Tumor/metabolismo
12.
Nat Cancer ; 2(3): 312-326, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33768209

RESUMEN

Amplification of MYCN is the driving oncogene in a subset of high-risk neuroblastoma. The MYCN protein and the Aurora-A kinase form a complex during S phase that stabilizes MYCN. Here we show that MYCN activates Aurora-A on chromatin, which phosphorylates histone H3 at serine 10 in S phase, promotes the deposition of histone H3.3 and suppresses R-loop formation. Inhibition of Aurora-A induces transcription-replication conflicts and activates the Ataxia telangiectasia and Rad3 related (ATR) kinase, which limits double-strand break accumulation upon Aurora-A inhibition. Combined inhibition of Aurora-A and ATR induces rampant tumor-specific apoptosis and tumor regression in mouse models of neuroblastoma, leading to permanent eradication in a subset of mice. The therapeutic efficacy is due to both tumor cell-intrinsic and immune cell-mediated mechanisms. We propose that targeting the ability of Aurora-A to resolve transcription-replication conflicts is an effective therapy for MYCN-driven neuroblastoma (141 words).


Asunto(s)
Aurora Quinasa A , Neuroblastoma , Animales , Apoptosis/genética , Aurora Quinasa A/genética , Línea Celular Tumoral , Ratones , Proteína Proto-Oncogénica N-Myc/genética , Neuroblastoma/tratamiento farmacológico
13.
Genesis ; 46(2): 104-11, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18257071

RESUMEN

Myc proteins are essential regulators of cellular growth and proliferation during normal development. Activating mutations in myc genes result in excessive growth and are frequently associated with human cancers. At the same time, forced expression of Myc sensitizes vertebrate cells towards different pro-apoptotic stimuli. Recently, the ability of overexpressed Myc to induce cell-autonomous apoptosis has been shown to be evolutionarily conserved in Drosophila Myc (dMyc). Here, we show that dMyc induced apoptosis is accompanied by the induction of Drosophila p53 mRNA, but that dp53 activity is not essential for dMyc's ability to induce apoptosis. Conversely, larvae carrying a hypomorphic dmyc mutation are more resistant to the apoptosis-promoting effects of X-irradiation. These data suggest that the control of apoptosis is a physiological function of Myc and that dMyc might play a role in the response to DNA damage.


Asunto(s)
Apoptosis , Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citología , Factores de Transcripción/metabolismo , Animales , Animales Modificados Genéticamente , Apoptosis/efectos de la radiación , Proteínas de Unión al ADN/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Ojo/metabolismo , Larva/citología , Larva/metabolismo , Mutación , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/metabolismo , Rayos X
14.
Mol Cell Biol ; 25(9): 3401-10, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15831447

RESUMEN

Myc is a transcription factor with diverse biological effects ranging from the control of cellular proliferation and growth to the induction of apoptosis. Here we present a comprehensive analysis of the transcriptional targets of the sole Myc ortholog in Drosophila melanogaster, dMyc. We show that the genes that are down-regulated in response to dmyc inhibition are largely identical to those that are up-regulated after dMyc overexpression and that many of them play a role in growth control. The promoter regions of these targets are characterized by the presence of the E-box sequence CACGTG, a known dMyc binding site. Surprisingly, a large subgroup of (functionally related) dMyc targets contains a single E-box located within the first 100 nucleotides after the transcription start site. The relevance of this E-box and its position was confirmed by a mutational analysis of a selected dMyc target and by the observation of its evolutionary conservation in a different Drosophila species, Drosophila pseudoobscura. These observations raise the possibility that a subset of Myc targets share a distinct regulatory mechanism.


Asunto(s)
Proteínas de Unión al ADN/fisiología , Proteínas de Drosophila/fisiología , Drosophila melanogaster/genética , Elementos E-Box/genética , Regulación de la Expresión Génica/genética , Genes de Insecto/genética , Factores de Transcripción/fisiología , Animales , Secuencia de Bases , Secuencia Conservada , Análisis Mutacional de ADN , Regulación hacia Abajo , Drosophila melanogaster/fisiología , Elementos E-Box/fisiología , Regulación de la Expresión Génica/fisiología , Genoma , Regiones Promotoras Genéticas/genética , Sitio de Iniciación de la Transcripción , Transcripción Genética , Regulación hacia Arriba
15.
Methods Mol Biol ; 420: 27-44, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18641939

RESUMEN

Drosophila melanogaster has long been a prime model organism for developmental biologists. During their work, they have established a large collection of techniques and reagents. This in turn has made fruit flies an attractive system for many other biomedical researchers who have otherwise no background in fly biology. This review intends to help Drosophila neophytes in setting up a fly lab. It briefly introduces the biological properties of fruit flies, describes the minimal equipment required for working with flies, and offers some basic advice for maintaining fly lines and setting up and analyzing experiments.


Asunto(s)
Biología Evolutiva/métodos , Drosophila melanogaster/fisiología , Animales , Cruzamientos Genéticos , Biología Evolutiva/instrumentación , Genética/instrumentación , Modelos Biológicos , Modelos Genéticos , Biología Molecular/instrumentación , Biología Molecular/métodos , Fenotipo
16.
Cancer Res ; 65(15): 6485-7, 2005 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-16061622

RESUMEN

The proto-oncogene Myc is already known to affect many cellular processes, but recent experiments in the fruit fly Drosophila melanogaster have revealed yet a new facet of Myc. Neighboring cells were shown to compare their Myc levels and the losers (cells with lower Myc activity) were actively eliminated. This phenomenon is called "cell competition," and it seems to be part of a developmental size and quality control program. Subversion of this mechanism may contribute to the transforming powers of Myc and possibly other oncogenes.


Asunto(s)
Comunicación Celular/fisiología , Proteínas Proto-Oncogénicas c-myc/fisiología , Animales , Procesos de Crecimiento Celular/fisiología , Drosophila
17.
Mol Cell Biol ; 34(10): 1878-91, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24615015

RESUMEN

Proper cell growth is a prerequisite for maintaining repeated cell divisions. Cells need to translate information about intracellular nutrient availability and growth cues from energy-sensing organs into growth-promoting processes, such as sufficient supply with ribosomes for protein synthesis. Mutations in the mushroom body miniature (mbm) gene impair proliferation of neural progenitor cells (neuroblasts) in the central brain of Drosophila melanogaster. Yet the molecular function of Mbm has so far been unknown. Here we show that mbm does not affect the molecular machinery controlling asymmetric cell division of neuroblasts but instead decreases their cell size. Mbm is a nucleolar protein required for small ribosomal subunit biogenesis in neuroblasts. Accordingly, levels of protein synthesis are reduced in mbm neuroblasts. Mbm expression is transcriptionally regulated by Myc, which, among other functions, relays information from nutrient-dependent signaling pathways to ribosomal gene expression. At the posttranslational level, Mbm becomes phosphorylated by casein kinase 2 (CK2), which has an impact on localization of the protein. We conclude that Mbm is a new part of the Myc target network involved in ribosome biogenesis, which, together with CK2-mediated signals, enables neuroblasts to synthesize sufficient amounts of proteins required for proper cell growth.


Asunto(s)
Quinasa de la Caseína II/metabolismo , Proteínas de Drosophila/fisiología , Drosophila melanogaster/metabolismo , Células-Madre Neurales/fisiología , Proteínas Nucleares/fisiología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Ribosomas/metabolismo , Animales , División Celular Asimétrica , Secuencia de Bases , Encéfalo/citología , Línea Celular , Nucléolo Celular/metabolismo , Tamaño de la Célula , Drosophila melanogaster/citología , Regulación de la Expresión Génica , Larva/citología , Larva/metabolismo , Masculino , Fosforilación , Procesamiento Proteico-Postraduccional , Procesamiento Postranscripcional del ARN , ARN Ribosómico/metabolismo , Transcriptoma
18.
Cold Spring Harb Perspect Med ; 3(10): a014324, 2013 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-24086064

RESUMEN

Drosophila contains a single MYC gene. Like its vertebrate homologs, it encodes a transcription factor that activates many targets, including prominently genes involved in ribosome biogenesis and translation. This activity makes Myc a central regulator of growth and/or proliferation of many cell types, such as imaginal disc cells, polyploid cells, stem cells, and blood cells. Importantly, not only does Myc act cell autonomously but it also affects the fate of adjacent cells and tissues. This potential of Myc is harnessed by many different signaling pathways, involving, among others, Wg, Dpp, Hpo, ecdysone, insulin, and mTOR.


Asunto(s)
Proteínas de Drosophila/genética , Drosophila/genética , Genes myc/fisiología , Animales , Células Sanguíneas/fisiología , Tamaño Corporal/genética , Proliferación Celular , Discos Imaginales/fisiología , Larva/genética , Transducción de Señal/genética , Células Madre/fisiología , Transcripción Genética/genética
19.
Dev Cell ; 18(6): 882-3, 2010 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-20627071

RESUMEN

In Drosophila imaginal discs, viable cells are outcompeted by their faster growing neighbors in a process called "cell competition." A new study in this issue of Developmental Cell identifies the membrane protein Flower as being specifically induced in the outcompeted cells and required for their ensuing apoptosis.

20.
Genes Cancer ; 1(6): 542-546, 2010 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-21072325

RESUMEN

Myc proteins control several cellular processes, including proliferation and growth, and they play an important role in human tumorigenesis. Several years ago, single homologs of Myc, its interaction partner Max, and its antagonist Mnt were identified in Drosophila melanogaster. Here, we review the function of this so-called Max network in fruit flies, with a particular emphasis on its most obvious biological activity: the control of cellular and organismal growth. We describe the molecular basis for this growth function, as well as the interaction of Myc with other pathways known to control growth, the insulin, TOR, and hippo pathways. In addition, Drosophila Myc also controls DNA replication and influences apoptosis, both cell-autonomously and non-autonomously, in a process known as cell competition. In the future, we expect that further functions of Myc will be uncovered and that genetic approaches will increasingly be used to characterize the evolutionarily conserved molecular mechanism of Myc action, thus also benefitting our understanding of Myc biology in vertebrates.

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