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1.
Nat Commun ; 13(1): 516, 2022 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-35082301

RESUMEN

Protein aggregation is a hallmark of neurodegeneration. Here, we find that Huntington's disease-related HTT-polyQ aggregation induces a cellular proteotoxic stress response, while ALS-related mutant FUS (mutFUS) aggregation leads to deteriorated proteostasis. Further exploring chaperone function as potential modifiers of pathological aggregation in these contexts, we reveal divergent effects of naturally-occurring chaperone isoforms on different aggregate types. We identify a complex of the full-length (FL) DNAJB14 and DNAJB12, that substantially protects from mutFUS aggregation, in an HSP70-dependent manner. Their naturally-occurring short isoforms, however, do not form a complex, and lose their ability to preclude mutFUS aggregation. In contrast, DNAJB12-short alleviates, while DNAJB12-FL aggravates, HTT-polyQ aggregation. DNAJB14-FL expression increases the mobility of mutFUS aggregates, and restores the deteriorated proteostasis in mutFUS aggregate-containing cells and primary neurons. Our results highlight a maladaptive cellular response to pathological aggregation, and reveal a layer of chaperone network complexity conferred by DNAJ isoforms, in regulation of different aggregate types.


Asunto(s)
Proteínas del Choque Térmico HSP40/metabolismo , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/metabolismo , Chaperonas Moleculares/metabolismo , Péptidos/metabolismo , Agregado de Proteínas , Proteína FUS de Unión a ARN/metabolismo , Células HEK293 , Proteínas del Choque Térmico HSP40/química , Humanos , Chaperonas Moleculares/química , Neuronas/metabolismo , Imagen Óptica , Isoformas de Proteínas/metabolismo , Proteostasis
2.
Int J Hyperthermia ; 38(1): 1495-1501, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34666607

RESUMEN

OBJECTIVES: Mutations in the human IQSEC2 gene are associated with drug-resistant epilepsy and severe behavioral dysfunction. We have focused on understanding one human IQSEC2 missense mutation (A350V) for which we have created a corresponding A350V IQSEC2 mouse model by CRISPR which demonstrates seizures when the mice are 15-20 days old and impaired social vocalizations in adulthood. We observed that a child with the A350V mutation stops having seizures when experiencing a fever of greater than 38 °C. In this study, we first sought to determine if we could recapitulate this phenomenon in A350V 15-20 day old mice using a previously established protocol to raise body temperature to 39 °C achieved by housing the mice at 37 °C. We then sought to determine if mice in whom seizure activity had been prevented as pups would develop social vocalization activity in adulthood. METHODS: 15-20 day old A350V male mice were housed either at 37 °C or 22 °C. Ultrasonic vocalizations of these mice were assessed at 8-10 weeks in response to a female stimulus. RESULTS: Housing of 15-20 day old A350V mice at 37 °C resulted in a reduction in lethal seizures to 2% (1/41) compared to 45% (48/108) in mice housed at 22 °C, p = 0.0001. Adult A350V mice who had been housed at 37 °C as pups displayed a significant improvement in the production of social vocalizations. CONCLUSION: Raising the body temperature by raising the ambient temperature might provide a means to reduce seizures associated with the A350V IQSEC2 mutation and thereby allow for an improved neurodevelopmental trajectory.


Asunto(s)
Factores de Intercambio de Guanina Nucleótido , Convulsiones/prevención & control , Temperatura , Vocalización Animal , Animales , Femenino , Factores de Intercambio de Guanina Nucleótido/genética , Vivienda , Masculino , Ratones , Proteínas del Tejido Nervioso
3.
Hum Genomics ; 12(1): 32, 2018 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-29945683

RESUMEN

Naturally occurring stress-induced transcriptional readthrough is a recently discovered phenomenon, in which stress conditions lead to dramatic induction of long transcripts as a result of transcription termination failure. In 2015, we reported the induction of such downstream of gene (DoG) containing transcripts upon osmotic stress in human cells, while others observed similar transcripts in virus-infected and cancer cells. Using the rigorous methodology Cap-Seq, we demonstrated that DoGs result from transcriptional readthrough, not de novo initiation. More recently, we presented a genome-wide comparison of NIH3T3 mouse cells subjected to osmotic, heat, and oxidative stress and concluded that massive induction of transcriptional readthrough is a hallmark of the mammalian stress response. In their recent letter, Huang and Liu in contrast claim that DoG transcripts result from novel transcription initiation near the ends of genes. Their conclusions rest on analyses of a publicly available transcription start site (TSS-Seq) dataset from unstressed NIH3T3 cells. Here, we present evidence that this dataset identifies not only true transcription start sites, TSSs, but also 5'-ends of numerous snoRNAs, which are generally processed from introns in mammalian cells. We show that failure to recognize these erroneous assignments in the TSS-Seq dataset, as well as ignoring published Cap-Seq data on TSS mapping during osmotic stress, have led to misinterpretation by Huang and Liu. We conclude that, contrary to the claims made by Huang and Liu, TSS-Seq reads near gene ends cannot explain the existence of DoGs, nor their stress-mediated induction. Rather it is, as we originally demonstrated, transcriptional readthrough that leads to the formation of DoGs.


Asunto(s)
ARN Nucleolar Pequeño/genética , Estrés Fisiológico/genética , Sitio de Iniciación de la Transcripción , Transcriptoma/genética , Animales , Regulación de la Expresión Génica/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Ratones , Células 3T3 NIH , Regiones Promotoras Genéticas
4.
Sci Signal ; 3(124): ra43, 2010 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-20516477

RESUMEN

Epidermal growth factor (EGF) stimulates cells by launching gene expression programs that are frequently deregulated in cancer. MicroRNAs, which attenuate gene expression by binding complementary regions in messenger RNAs, are broadly implicated in cancer. Using genome-wide approaches, we showed that EGF stimulation initiates a coordinated transcriptional program of microRNAs and transcription factors. The earliest event involved a decrease in the abundance of a subset of 23 microRNAs. This step permitted rapid induction of oncogenic transcription factors, such as c-FOS, encoded by immediate early genes. In line with roles as suppressors of EGF receptor (EGFR) signaling, we report that the abundance of this early subset of microRNAs is decreased in breast and in brain tumors driven by the EGFR or the closely related HER2. These findings identify specific microRNAs as attenuators of growth factor signaling and oncogenesis.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Neoplasias de la Mama/metabolismo , Factor de Crecimiento Epidérmico/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , MicroARNs/biosíntesis , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Neoplásico/biosíntesis , Línea Celular Tumoral , Factor de Crecimiento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Transducción de Señal/efectos de los fármacos
5.
Trends Genet ; 26(6): 253-9, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20417576

RESUMEN

MicroRNAs (miRNAs) appear to be key players in the maintenance of genomic integrity. Recent evidence implies that cancers often avoid miRNA-mediated regulation, and global repression of miRNAs is associated with increased tumorigenicity. Here we suggest that miRNAs are directly involved in the maintenance of genomic integrity through global repression of transposable elements (TEs), whose expression and transposition are well-documented causes of genomic instability in mammalian somatic tissues. Hence, one outcome of the tumor's ability to avoid miRNA-mediated regulation might be the enhancement of genomic instability and mutability due to derepression of TEs. We outline possible mechanisms underlying TE repression by miRNAs, including post-transcriptional silencing and transcriptional silencing through DNA and histone methylation. This hypothesis calls into consideration the need to study the role of miRNAs and the RNAi machinery in the nucleus, and specifically their impact on the maintenance of genomic integrity in the context of cancer.


Asunto(s)
Elementos Transponibles de ADN , MicroARNs/genética , Neoplasias/genética , Animales , Regulación Neoplásica de la Expresión Génica , Inestabilidad Genómica , Humanos , Neoplasias/patología , Interferencia de ARN , Transcripción Genética
6.
Aging (Albany NY) ; 1(9): 762-70, 2009 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-20157565

RESUMEN

miRNAs function as a critical regulatory layer in development, differentiation, and the maintenance of cell fate. Depletion of miRNAs from embryonic stem cells impairs their differentiation capacity. Total elimination of miRNAs leads to premature senescence in normal cells and tissues through activation of the DNA-damage checkpoint, whereas ablation of miRNAs in cancer cell lines results in an opposite effect, enhancing their tumorigenic potential. Here we compile evidence from the literature that point at miRNAs as key players in the maintenance of genomic integrity and proper cell fate. There is an apparent gap between our understanding of the subtle way by which miRNAs modulate protein levels, and their profound impact on cell fate. We propose that examining miRNAs in the context of the regulatory transcriptional and post-transcriptional networks they are embedded in may provide a broader view of their role in controlling cell fate.


Asunto(s)
Diferenciación Celular/genética , Regulación de la Expresión Génica , MicroARNs/genética , MicroARNs/metabolismo , Transcripción Genética , Animales , Transformación Celular Neoplásica/genética , Senescencia Celular/genética , Inestabilidad Genómica/genética , Humanos
7.
Mol Syst Biol ; 4: 229, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-19034270

RESUMEN

Normal cell growth is governed by a complicated biological system, featuring multiple levels of control, often deregulated in cancers. The role of microRNAs (miRNAs) in the control of gene expression is now increasingly appreciated, yet their involvement in controlling cell proliferation is still not well understood. Here we investigated the mammalian cell proliferation control network consisting of transcriptional regulators, E2F and p53, their targets and a family of 15 miRNAs. Indicative of their significance, expression of these miRNAs is downregulated in senescent cells and in breast cancers harboring wild-type p53. These miRNAs are repressed by p53 in an E2F1-mediated manner. Furthermore, we show that these miRNAs silence antiproliferative genes, which themselves are E2F1 targets. Thus, miRNAs and transcriptional regulators appear to cooperate in the framework of a multi-gene transcriptional and post-transcriptional feed-forward loop. Finally, we show that, similarly to p53 inactivation, overexpression of representative miRNAs promotes proliferation and delays senescence, manifesting the detrimental phenotypic consequence of perturbations in this circuit. Taken together, these findings position miRNAs as novel key players in the mammalian cellular proliferation network.


Asunto(s)
Proliferación Celular , Factores de Transcripción E2F/fisiología , Redes Reguladoras de Genes/fisiología , MicroARNs/fisiología , Proteína p53 Supresora de Tumor/fisiología , Animales , Neoplasias de la Mama , Senescencia Celular , Factor de Transcripción E2F1 , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Biología de Sistemas
8.
Clin Cancer Res ; 12(7 Pt 1): 2014-24, 2006 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-16609010

RESUMEN

PURPOSE: The aim of this study was to investigate the role of p53 in regulating micro-RNA (miRNA) expression due to its function as a transcription factor. In addition, p53 may also affect other cellular mRNA gene expression at the translational level either via its mediated miRNAs or due to its RNA-binding function. EXPERIMENTAL DESIGN: The possible interaction between p53 and miRNAs in regulating gene expression was investigated using human colon cancer HCT-116 (wt-p53) and HCT-116 (null-p53) cell lines. The effect of p53 on the expression of miRNAs was investigated using miRNA expression array and real-time quantitative reverse transcription-PCR analysis. RESULTS: Our investigation indicated that the expression levels of a number of miRNAs were affected by wt-p53. Down-regulation of wt-p53 via small interfering RNA abolished the effect of wt-p53 in regulating miRNAs in HCT-116 (wt-p53) cells. Global sequence analysis revealed that over 46% of the 326 miRNA putative promoters contain potential p53-binding sites, suggesting that some of these miRNAs were potentially regulated directly by wt-p53. In addition, the expression levels of steady-state total mRNAs and actively translated mRNA transcripts were quantified by high-density microarray gene expression analysis. The results indicated that nearly 200 cellular mRNA transcripts were regulated at the posttranscriptional level, and sequence analysis revealed that some of these mRNAs may be potential targets of miRNAs, including translation initiation factor eIF-5A, eIF-4A, and protein phosphatase 1. CONCLUSION: To the best of our knowledge, this is the first report demonstrating that wt-p53 and miRNAs interact in influencing gene expression and providing insights of how p53 regulates genes at multiple levels via unique mechanisms.


Asunto(s)
Neoplasias del Colon/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , ARN Mensajero/genética , Proteína p53 Supresora de Tumor/metabolismo , Línea Celular Tumoral , Neoplasias del Colon/metabolismo , Perfilación de la Expresión Génica , Humanos , MicroARNs/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transcripción Genética
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