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1.
Proc Natl Acad Sci U S A ; 119(14): e2122174119, 2022 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-35344424

RESUMEN

Replication-dependent (RD) histones are deposited onto human cytomegalovirus (HCMV) genomes at the start of infection. We examined how HCMV affects the de novo production of RD histones and found that viral infection blocked the accumulation of RD histone mRNAs that normally occurs during the S phase. Furthermore, RD histone mRNAs present in HCMV-infected cells did not undergo the unique 3' processing required for their normal nuclear export and translation. The protein that orchestrates processing in the nucleus, stem loop­binding protein (SLBP), was found predominantly in the cytoplasm, and RD histone proteins were not de novo synthesized in HCMV-infected cells. Intriguingly, however, we found that SLBP was required for the efficient synthesis and assembly of infectious progeny virions. We conclude that HCMV infection attenuates RD histone mRNA accumulation and processing and the de novo protein synthesis of the RD histones, while utilizing SLBP for an alternative purpose to support infectious virion production.


Asunto(s)
Infecciones por Citomegalovirus , Citomegalovirus , Histonas , Replicación Viral , División Celular , Citomegalovirus/genética , Citomegalovirus/fisiología , Infecciones por Citomegalovirus/virología , Replicación del ADN , Histonas/metabolismo , Humanos
2.
J Virol ; 86(2): 854-64, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22090104

RESUMEN

Viruses are appreciated as etiological agents of certain human tumors, but the number of different cancer types induced or exacerbated by viral infections is unknown. Glioblastoma multiforme (GBM)/astrocytoma grade IV is a malignant and lethal brain cancer of unknown origin. Over the past decade, several studies have searched for the presence of a prominent herpesvirus, human cytomegalovirus (HCMV), in GBM samples. While some have detected HCMV DNA, RNA, and proteins in GBM tissues, others have not. Therefore, any purported association of HCMV with GBM remains controversial. In most of the previous studies, only one or a select few viral targets were analyzed. Thus, it remains unclear the extent to which the entire viral genome was present when detected. Here we report the results of a survey of GBM specimens for as many as 20 different regions of the HCMV genome. Our findings indicate that multiple HCMV loci are statistically more likely to be found in GBM samples than in other brain tumors or epileptic brain specimens and that the viral genome was more often detected in frozen samples than in paraffin-embedded archival tissue samples. Finally, our experimental results indicate that cellular genomes substantially outnumber viral genomes in HCMV-positive GBM specimens, likely indicating that only a minority of the cells found in such samples harbor viral DNA. These data argue for the association of HCMV with GBM, defining the virus as oncoaccessory. Furthermore, they imply that, were HCMV to enhance the growth or survival of a tumor (i.e., if it is oncomodulatory), it would likely do so through mechanisms distinct from classic tumor viruses that express transforming viral oncoproteins in the overwhelming majority of tumor cells.


Asunto(s)
Neoplasias Encefálicas/virología , Infecciones por Citomegalovirus/virología , Citomegalovirus/genética , Citomegalovirus/aislamiento & purificación , Genoma Viral , Glioblastoma/virología , Neoplasias Encefálicas/patología , Infecciones por Citomegalovirus/patología , ADN Viral/genética , Glioblastoma/patología , Humanos , Estudios Retrospectivos
3.
Cancer Res ; 66(6): 2889-92, 2006 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-16540633

RESUMEN

Activation of the phosphoinositide 3-kinase (PI3K)/Akt cell survival pathway in many cancers makes it an appealing target for therapeutic development. However, because this pathway also has an important role in the survival of normal cells, tactics to achieve cancer selectivity may prove important. We recently showed that the cancer-selective proapoptotic protein Par-4 is a key target for inactivation by PI3K/Akt signaling. Additionally, we found that Par-4 participates in mediating apoptosis by PTEN, the tumor suppressor responsible for blocking PI3K/Akt signaling. As a central player in cancer cell survival, Par-4 may provide a useful focus for the development of cancer-selective therapeutics.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Activación Enzimática , Humanos , Neoplasias/patología , Transducción de Señal
4.
Methods Enzymol ; 407: 422-42, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16757343

RESUMEN

Oncogenic Ras causes down-regulation of the proapoptotic tumor suppressor gene Par-4. Replenishment of the basal levels of Par-4 results in inhibition of Ras-inducible cellular transformation. Moreover, overexpression of Par-4 (twofold to fourfold over basal levels) results in apoptosis of cells expressing oncogenic Ras. Par-4 does not, on its own, induce apoptosis in immortalized or nontransformed cells. This chapter describes the key methods used for analysis of Par-4 down-regulation by oncogenic Ras, which can be extended to study most genes whose down-regulation by oncogenic Ras is critical for oncogenic transformation and cell survival.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas ras/fisiología , Animales , Transformación Celular Neoplásica , Regulación hacia Abajo , Electroforesis en Gel de Poliacrilamida , Regulación de la Expresión Génica , Ratones , Células 3T3 NIH , Transfección
5.
Ann N Y Acad Sci ; 1059: 76-85, 2005 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16382046

RESUMEN

Prostate apoptosis response-4 (Par-4) is a unique pro-apoptotic protein that selectively induces apoptosis in cancer cells. Moreover, Par-4 sensitizes cells to the action of diverse apoptotic stimuli and causes tumor regression. This review discusses the prominent structural and functional features of Par-4 and the multiple levels of regulation of its apoptotic function, all of which can be utilized to develop targeted cancer therapy.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis , Supervivencia Celular , Humanos , Modelos Genéticos , Neoplasias/tratamiento farmacológico
7.
Cancer Res ; 68(15): 6190-8, 2008 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-18676842

RESUMEN

The regulation of DNA relaxation by topoisomerase 1 (TOP1) is essential for DNA replication, transcription, and recombination events. TOP1 activity is elevated in cancer cells, yet the regulatory mechanism restraining its activity is not understood. We present evidence that the tumor suppressor protein prostate apoptosis response-4 (Par-4) directly binds to TOP1 and attenuates its DNA relaxation activity. Unlike camptothecin, which binds at the TOP1-DNA interface to form cleavage complexes, Par-4 interacts with TOP1 via its leucine zipper domain and sequesters TOP1 from the DNA. Par-4 knockdown by RNA interference enhances DNA relaxation and gene transcription activities and promotes cellular transformation in a TOP1-dependent manner. Conversely, attenuation of TOP1 activity either by RNA interference or Par-4 overexpression impedes DNA relaxation, cell cycle progression, and gene transcription activities and inhibits transformation. Collectively, our findings suggest that Par-4 serves as an intracellular repressor of TOP1 catalytic activity and regulates DNA topology to suppress cellular transformation.


Asunto(s)
ADN-Topoisomerasas de Tipo I/metabolismo , ADN/metabolismo , Receptores de Trombina/metabolismo , Animales , Secuencia de Bases , Línea Celular Transformada , ADN/química , Cartilla de ADN , Ensayo de Cambio de Movilidad Electroforética , Humanos , Inmunohistoquímica , Inmunoprecipitación , Leucina Zippers , Ratones , Células 3T3 NIH , Unión Proteica
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