The Tal1 oncoprotein inhibits E47-mediated transcription. Mechanism of inhibition.
The Tal1 oncogene is a class II basic helix-loop-helix (bHLH) transcription factor, overexpressed in as much as 60% of T cell acute lymphoblastic leukemia cases. Like other class II bHLH proteins, Tal1 can heterodimerize with the class I bHLH proteins, such as E47, and bind to a DNA recognition sequence termed E box. Therefore, it is believed that the oncogenic capacity of Tal1 lies in its ability, as a heterodimer with E47, to activate aberrantly a set of "leukemogenic" genes in T cells. However, compared with E47 homodimers, Tal1/E47 heterodimers are very poor transactivators. Thus the effect of Tal1 is actually to inhibit E47 homodimer activity. Here we propose that the transforming properties of Tal1 are the result of its ability to inhibit E47 activity. We address the mechanism of Tal1 inhibition and demonstrate that Tal1/E47 heterodimers cannot activate transcription because their respective activation domains are incompatible. Furthermore, we present data showing that Tal1 can inhibit E47-mediated activation of the CIP1 gene. Finally, we demonstrate that Tal1 inhibits E47 activity in leukemic T cells.
Park
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Department of Cell Biology, New York University Medical Center, New York, New York 10016, USA.
Sun
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XH
D051792:Basic Helix-Loop-Helix Proteins; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019281:Dimerization; D006367:HeLa Cells; D006801:Humans; D011485:Protein Binding; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins / Q000235:genetics; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004247:DNA; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; C493956:CDKN1A protein, human; C544912:TCF7L1 protein, human; C067143:TAL1 protein, human