期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 20, 期 6, 页码 2248-2259出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.20.6.2248-2259.2000
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资金
- NATIONAL CANCER INSTITUTE [P30CA068485] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL049118] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK020593, P60DK020593] Funding Source: NIH RePORTER
- NCI NIH HHS [P30 CA068485, CA68485] Funding Source: Medline
- NHLBI NIH HHS [R01 HL049118, R01 HL49118] Funding Source: Medline
- NIDDK NIH HHS [DK20593, P30 DK020593] Funding Source: Medline
Activation of the TAL1 (or SCL) gene is the most frequent gain-of-function mutation in T-cell acute Lymphoblastic leukemia (T-ALL), TALI 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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