mSin3A regulates murine erythroleukemia cell differentiation through association with the TAL1 (or SCL) transcription factor

Suming Huang, Stephen J. Brandt

Research output: Contribution to journalArticle

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Abstract

Activation of the TAL1 (or SCL) gene is the most frequent gain-of- function mutation in T-cell acute lymphoblastic leukemia (T-ALL). TAL1 belongs to the basic helix-loop-helix (HLH) family of transcription factors that bind as heterodimers with the E2A and HEB/HTF4 gene products to a nucleotide sequence motif termed the E-box. Reported to act both as an activator and as a repressor of transcription, the mechanisms underlying TAL1-regulated gene expression are poorly understood. We report here that the corepressor mSin3A is associated with TAL1 in murine erythroleukemia (MEL) and human T-ALL cells. Interaction mapping showed that the basic-HLH domain of TAL1 was both necessary and sufficient for TAL1-mSin3A interaction. TAL1 was found, in addition, to interact with the histone deacetylase HDAC1 in vitro and in vivo, and a specific histone deacetylase inhibitor, trichostatin A (TSA), relieved TAL1-mediated repression of an E-box-containing promoter and a GAL4 reporter linked to a thymidine kinase minimal promoter. Further, TAL1 association with mSin3A and HDAC1 declined during dimethyl sulfoxide- induced differentiation of MEL cells in parallel with a decrease in mSin3A abundance. Finally, TSA had a synergistic effect with enforced TAL1 expression in stimulating MEL cells to differentiate, while constitutive expression of mSin3A inhibited MEL cell differentiation. These results demonstrate that a corepressor complex containing mSin3A and HDAC1 interacts with TAL1 and restricts its function in erythroid differentiation. This also has implications for this transcription factor's actions in leukemogenesis.

Original languageEnglish (US)
Pages (from-to)2248-2259
Number of pages12
JournalMolecular and cellular biology
Volume20
Issue number6
DOIs
StatePublished - Mar 1 2000

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Leukemia, Erythroblastic, Acute
Cell Differentiation
trichostatin A
Transcription Factors
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Co-Repressor Proteins
Helix-Loop-Helix Motifs
Histone Deacetylase 1
Basic Helix-Loop-Helix Transcription Factors
Nucleotide Motifs
Histone Deacetylase Inhibitors
Thymidine Kinase
Dimethyl Sulfoxide
Genes
Gene Expression
Mutation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

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abstract = "Activation of the TAL1 (or SCL) gene is the most frequent gain-of- function mutation in T-cell acute lymphoblastic leukemia (T-ALL). TAL1 belongs to the basic helix-loop-helix (HLH) family of transcription factors that bind as heterodimers with the E2A and HEB/HTF4 gene products to a nucleotide sequence motif termed the E-box. Reported to act both as an activator and as a repressor of transcription, the mechanisms underlying TAL1-regulated gene expression are poorly understood. We report here that the corepressor mSin3A is associated with TAL1 in murine erythroleukemia (MEL) and human T-ALL cells. Interaction mapping showed that the basic-HLH domain of TAL1 was both necessary and sufficient for TAL1-mSin3A interaction. TAL1 was found, in addition, to interact with the histone deacetylase HDAC1 in vitro and in vivo, and a specific histone deacetylase inhibitor, trichostatin A (TSA), relieved TAL1-mediated repression of an E-box-containing promoter and a GAL4 reporter linked to a thymidine kinase minimal promoter. Further, TAL1 association with mSin3A and HDAC1 declined during dimethyl sulfoxide- induced differentiation of MEL cells in parallel with a decrease in mSin3A abundance. Finally, TSA had a synergistic effect with enforced TAL1 expression in stimulating MEL cells to differentiate, while constitutive expression of mSin3A inhibited MEL cell differentiation. These results demonstrate that a corepressor complex containing mSin3A and HDAC1 interacts with TAL1 and restricts its function in erythroid differentiation. This also has implications for this transcription factor's actions in leukemogenesis.",
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mSin3A regulates murine erythroleukemia cell differentiation through association with the TAL1 (or SCL) transcription factor. / Huang, Suming; Brandt, Stephen J.

In: Molecular and cellular biology, Vol. 20, No. 6, 01.03.2000, p. 2248-2259.

Research output: Contribution to journalArticle

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