Alternative splicing: an emerging topic in molecular and clinical oncology

Pajares, María J.; Ezponda, Teresa; Catena, Raúl; Calvo, Alfonso; Pı́o, Rubén; Montuenga, Luis M.

doi:10.1016/s1470-2045(07)70104-3

Cited by 233 publications

(197 citation statements)

References 68 publications

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“…23 Aberrant splicing has been related to activation of oncogenes and inhibition of tumorsuppressor genes in a variety of human cancers. 24 Accumulating evidence suggests that cellular splicing machinery is changed during oncogenic transformation of cells, although the mechanism for these changes remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…24 Accumulating evidence suggests that cellular splicing machinery is changed during oncogenic transformation of cells, although the mechanism for these changes remains to be elucidated. 23,25 Being a cause of cancer, an alternative splicing variant must presumably be expressed at significant high level compared with the properly splicing products. 24 However, most aberrant mRNAs are degraded by nonsense-mediated mRNA decay pathway; 26 some new mRNA species can bring about a reduction of normal protein levels or produce different protein isoforms with potentially tumorigenic properties.…”

Section: Discussionmentioning

confidence: 99%

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Identification of alternatively spliced GRIM-19 mRNA in kidney cancer tissues

Cao

2010

J Hum Genet

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of alternatively spliced GRIM-19 mRNA in kidney cancer tissues

Cao

2010

J Hum Genet

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“…This could be applied to any exon inclusion/skipping control, provided that a suitable modified U7 snRNA is available. Given that alternative splicing concerns more than 60% of human genes 1 and that it is of major importance for the regulation of gene expression and proteome diversity, this tool represents an unprecedented opportunity to investigate the importance of individual splice variants on a cell's physiology, for instance related to apoptosis, 25 cancer 26 or specific cell functions, for example, in certain types of neurons. 27 The combined facts that this is a two-vector system, that its very sharp induction properties make it difficult to obtain intermediate expression levels (Figure 3) and that its properties in vivo have yet to be analysed do not presently make it an option for use in a human therapeutic setting.…”

Section: Discussionmentioning

confidence: 99%

Doxycycline-controlled splicing modulation by regulated antisense U7 snRNA expression cassettes

2008

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Many diseases affect pre-mRNA splicing, and alternative splicing is a major source of proteome diversity and an important mechanism for modulating gene expression. The ability to regulate a specific splicing event is therefore desirable; for example, to understand splicing-associated pathologies. We have developed methods based on modified U7 snRNAs, which allow us to induce efficient skipping or inclusion of selected exons. Here, we have adapted these U7 tools to a regulatable system that relies on a doxycyclinesensitive version of the Krü ppel-associated box (KRAB)/ KAP1 transcriptional silencing. Co-transduction of target cells with two lentiviral vectors, one carrying the KRAB protein and the other the regulatable U7 cassette, allows a tight regulation of the modified U7 snRNA. No leakage is observed in the repressed state, whereas full induction can be obtained with doxycycline in ng ml À1 concentrations. Only a few days are necessary for a full switch, and the induction/ repression can be repeated over several cycles without noticeable loss of control. Importantly, the U7 expression correlates with splicing correction, as shown for the skipping of an aberrant b-globin exon created by a thalassaemic mutation and the promotion of exon 7 inclusion in the human SMN2 gene, an important therapeutic target for spinal muscular atrophy.

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“…Se sabe que las células tumorales poseen una gran inestabilidad genómica, lo que les confiere la enorme plasticidad que les caracteriza 46 y que uno de los muchos factores que contribuye a esta inestabilidad genómica es la desregulación del proceso de splicing (corte y empalme) 47,48 .…”

Section: Splicing Alternativounclassified

“…En los últimos años se han descrito alteraciones en splicing alternativo específicas de células tumorales, sin detectarse ninguna mutación en el gen afectado, que está asociado a una alteración en elementos trans (factores reguladores del splicing que pueden aumentar o disminuir en las células tumorales). También puede variar la localización y la actividad de estos factores, favoreciéndose ciertas isoformas producidas por splicing alternativo 48 .…”

Section: Splicing Alternativounclassified

Vacuna idiotípica en el tratamiento del linfoma folicular: situación actual y perspectivas futuras

Zabalegui¹,

Cerio²,

Inogés³

et al. 2009

Anales Sis San Navarra

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RESUMENEl linfoma folicular (LF) está considerado como el segundo tipo de linfoma no-Hodgkin más común, representando más del 20% del total de los linfomas. Es una enfermedad de progresión lenta y curso indolente en la que, a pesar de la buena respuesta al tratamiento, las recaídas son muy frecuentes y cada vez es más difí-cil conseguir respuestas completas. Por ello, se puede considerar que hasta el momento, el LF es incurable. La búsqueda continua de nuevas estrategias terapéu-ticas en enfermedades neoplásicas, junto con un mejor conocimiento del sistema inmunitario, ha llevado a la aparición de una nueva disciplina, conocida con el nombre de inmunoterapia, que aprovecha la capacidad del sistema inmunitario de atacar lo extraño sin dañar lo propio. El LF es un tumor muy apropiado para este tipo de tratamiento por presentar un antígeno específi-co de tumor: el idiotipo de la inmunoglobulina monoclonal expresada en la membrana de todas las células tumorales. Se han realizado diversos estudios en los que se ha probado la inmunoterapia como tratamiento complementario al tratamiento convencional. Recientemente, nuestro grupo ha publicado un estudio en el que se observa claramente que los resultados que se obtienen tras la vacunación idiotípica, cuando se consigue la inmunización adecuada del paciente, son mejores que los obtenidos con quimioterapia sola. En este sentido, es necesario seguir investigando para aclarar si la vacunación idiotípica pudiera no sólo mantener remisiones completas duraderas en los pacientes vacunados, sino incluso conseguir la curación de los mismos. Por ello, resulta interesante abordar un mejor planteamiento de los ensayos clínicos, la mejora de la producción de la vacuna y el estudio de mecanismos de la célula tumoral capaces de modificar la inmunoglobulina específica del tumor.Palabras clave. Linfoma folicular. Inmunoterapia. Vacuna idiotípica. Glicosilación. Splicing alternativo. ABSTRACTFollicular lymphoma is the second most prevalent non-Hodgkin lymphoma, representing 20% of all lymphomas. Follicular lymphoma is an indolent disease with a slow progression in which, although exhibiting a good response to treatment, relapse is very frequent and complete remission is not easy to maintain. Therefore, the disease is regarded as incurable. The search for new therapeutic strategies, together with a better understanding of the immune system, has led to the emergence of a new treatment named immunotherapy. Follicular lymphoma is a malignancy suitable for this kind of treatment given the fact that it is characterized by presenting a unique tumour-specific antigen: the idiotype of the monoclonal immunoglobulin displayed on the membrane of tumour cells. Several studies have been conducted to test immunotherapy as complementary to conventional treatment. In a previous study by our group, a clear benefit was evident is obtained after idiotypic vaccination, when an adequate immunization of the patient is obtained, in comparison to chemotherapy alone. In this sense, analysis is needed of whether idi...

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Alternative splicing: an emerging topic in molecular and clinical oncology

Cited by 233 publications

References 68 publications

Identification of alternatively spliced GRIM-19 mRNA in kidney cancer tissues

Identification of alternatively spliced GRIM-19 mRNA in kidney cancer tissues

Doxycycline-controlled splicing modulation by regulated antisense U7 snRNA expression cassettes

Vacuna idiotípica en el tratamiento del linfoma folicular: situación actual y perspectivas futuras

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