Conserved sequences in the final intron of MDM2 are essential for the regulation of alternative splicing of MDM2 in response to stress.
Exp Cell Res
; 315(19): 3419-32, 2009 Nov 15.
Article
en En
| MEDLINE
| ID: mdl-19631207
ABSTRACT
Alternative splicing plays a fundamental role in generating proteome diversity and is critical in regulation of eukaryotic gene expression. It is estimated that 50% of disease-causing mutations alter splicing efficiency and/or patterns of splicing. An alternatively spliced form of murine double-minute 2, MDM2-ALT1, is associated with pediatric rhabdomyosarcoma (RMS) at high frequency in primary human tumors and RMS cell lines. We have identified that this isoform can be induced in response to specific types of stress (UV and cisplatin). However, the mechanism of alternative splicing of MDM2 in human cancer is unknown. Using UV and cisplatin to model alternative splicing of the MDM2 gene, we have developed a damage-inducible in vitro splicing system. This system employs an MDM2 minigene that mimics the damage-induced alternative splicing observed in vivo. Using this in vitro splicing system, we have shown that conserved intronic sequences in intron 11 of MDM2 are required for normal splicing. Furthermore, we showed that these intronic elements are also required for the regulated damage-induced alternative splicing of MDM2. The use of this novel damage-inducible system will allow for the systematic identification of regulatory elements and factors involved in the splicing regulation of the MDM2 gene in response to stress. This study has implications for identification of novel intervention points for development of future therapeutics for rhabdomyosarcoma.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Estrés Fisiológico
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Intrones
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Secuencia Conservada
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Empalme Alternativo
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Proteínas Proto-Oncogénicas c-mdm2
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Exp Cell Res
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos