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Downregulation of the Spi-1/PU.1 oncogene induces the expression of TRIM10/HERF1, a key factor required for terminal erythroid cell differentiation and survival
- Source :
- Cell research. 18(8)
- Publication Year :
- 2008
-
Abstract
- 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.
- Subjects :
- Erythrocytes
Cell Survival
RNA Splicing
Down-Regulation
Biology
Tripartite Motif Proteins
Exon
Hemoglobins
Mice
Downregulation and upregulation
Erythroid Cells
Transcription (biology)
Cell Line, Tumor
Histocompatibility Antigens
Proto-Oncogene Proteins
Gene silencing
Animals
Dimethyl Sulfoxide
Molecular Biology
Messenger RNA
Gene knockdown
Oncogene
Proto-Oncogene Protein c-fli-1
Microfilament Proteins
Intracellular Signaling Peptides and Proteins
Cell Differentiation
Cell Biology
Blood Proteins
Exons
Molecular biology
Hematopoiesis
Up-Regulation
RNA splicing
Trans-Activators
RNA Interference
Carrier Proteins
Signal Transduction
Subjects
Details
- ISSN :
- 17487838
- Volume :
- 18
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Cell research
- Accession number :
- edsair.doi.dedup.....13f63eaecf1da2a22466d70a21afacdc