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1.
Oncogene ; 23(4): 920-7, 2004 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-14647452

RESUMO

The inclusion of exon 16 in mature protein 4.1R mRNA arises from a stage-specific splicing event that occurs during late erythroid development. We have shown that mouse erythroleukemia (MEL) cells reproduce this erythroid-specific splicing event upon induction of differentiation. We here found that this splicing event is regulated specifically in erythroleukemic cells that have the potential to differentiate and produce hemoglobin, regardless of the nature of the differentiation inducer. Knowing that dysregulated expression of spi-1/pu.1 and fli-1 oncogenes is involved in MEL cell differentiation arrest, we looked at their effect on exon 16 erythroid splicing. We found that exon 16 inclusion requires Spi-1/PU.1 shutdown in MEL cells, and that enforced expression of Spi-1/PU.1 inhibits exon selection, regardless of the presence or absence of a chemical inducer. By contrast, endogenous overexpression or enforced expression of Fli-1 has no effect on exon selection. We further showed that Spi-1/PU.1 acts similarly on the endogenous and on a transfected exon 16, suggesting a promoter-independent effect of Spi-1/PU.1 on splicing regulation. This study provides the first evidence that Spi-1/PU.1 displays the unique property, not shared with Fli-1, to inhibit erythroid-specific pre-mRNA splicing in erythroleukemia cell context.


Assuntos
Processamento Alternativo/fisiologia , Proteínas de Ligação a DNA/fisiologia , Leucemia Eritroblástica Aguda/genética , Proteínas Proto-Oncogênicas/fisiologia , Precursores de RNA/genética , RNA Mensageiro/genética , Transativadores/fisiologia , Animais , Sequência de Bases , Diferenciação Celular , Primers do DNA , Éxons , Leucemia Eritroblástica Aguda/patologia , Camundongos , Proteína Proto-Oncogênica c-fli-1 , Células Tumorais Cultivadas
2.
Med Sci (Paris) ; 20(11): 1014-9, 2004 Nov.
Artigo em Francês | MEDLINE | ID: mdl-15525498

RESUMO

Oncogene activity ranges from transduction signals to transcription factors. Altered expression of oncogenes, either by chromosomal translocation, proviral insertion or point mutations, can lead to tumor formation. More specifically, data accumulated through the last two decades have shown that disregulation of oncogenic transcription factors can interfere with regulatory cascades that control the growth, differentiation, and survival of normal cells. There is also evidence that alterations of oncogene activity are associated with pre-mRNA splicing defects. The insights gained from the pivotal role of RNA polymerase II in coupling transcription and splicing have instigated a new line of research regarding the possible role of oncogenic transcription factors in pre-mRNA splicing regulation. This review focuses on recent advances addressing this question. Understanding the impact of alterations in the expression and/or function of oncogenes have important prognostic implications that can guide the design of new therapeutic drugs to promote differentiation and/or apoptosis over cell proliferation.


Assuntos
Oncogenes , Splicing de RNA , Fatores de Transcrição/farmacologia , Apoptose , Diferenciação Celular , Transformação Celular Neoplásica , Regulação da Expressão Gênica , Humanos , Transdução de Sinais , Fatores de Transcrição/genética
3.
Cell Res ; 18(8): 834-45, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18560381

RESUMO

Sustained expression of the Spi-1/PU.1 and Fli-1 oncoproteins blocks globin gene activation in mouse erythroleukemia cells; however, only Spi-1/PU.1 expression inhibits the inclusion of exon 16 in the mature 4.1R mRNA. This splicing event is crucial for a functional 4.1R protein and, therefore, for red blood cell membrane integrity. This report demonstrates that Spi-1/PU.1 downregulation induces the activation of TRIM10/hematopoietic RING finger 1 (HERF1), a member of the tripartite motif (TRIM)/RBCC protein family needed for globin gene transcription. Additionally, we demonstrate that TRIM10/HERF1 is required for the regulated splicing of exon 16 during late erythroid differentiation. Using inducible overexpression and silencing approaches, we found that: (1) TRIM10/HERF1 knockdown inhibits hemoglobin production and exon splicing and triggers cell apoptosis in dimethylsulfoxide (DMSO)-induced cells; (2) TRIM10/HERF1 upregulation is required but is insufficient on its own to activate exon retention; (3) Fli-1 has no effect on TRIM10/HERF1 expression, whereas either DMSO-induced downregulation or shRNA-knockdown of Spi-1/PU.1 expression is sufficient to activate TRIM10/HERF1 expression; and (4) Spi-1/PU.1 knockdown triggers both the transcription and the splicing events independently of the chemical induction. Altogether, these data indicate that primary Spi-1/PU.1 downregulation acts on late erythroid differentiation through at least two pathways, one of which requires TRIM10/HERF1 upregulation and parallels the Spi-1/PU.1-induced Fli-1 shutoff regulatory cascade.


Assuntos
Diferenciação Celular/genética , Células Eritroides/metabolismo , Hematopoese/fisiologia , Antígenos de Histocompatibilidade/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Animais , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Dimetil Sulfóxido/farmacologia , Regulação para Baixo/genética , Eritrócitos/citologia , Eritrócitos/metabolismo , Células Eritroides/citologia , Éxons/genética , Hematopoese/genética , Hemoglobinas/biossíntese , Antígenos de Histocompatibilidade/genética , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Proteínas dos Microfilamentos , Proteína Proto-Oncogênica c-fli-1/genética , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteínas Proto-Oncogênicas/genética , Interferência de RNA , Splicing de RNA/genética , Transdução de Sinais/genética , Transativadores/genética , Proteínas com Motivo Tripartido , Regulação para Cima/genética
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