Inhibition of cellular differentiation by the SCL/tal oncoprotein: transcriptional repression by an Id-like mechanism.
In cases of T-cell acute lymphoblastic leukemia (T-ALL), the basic helix-loop-helix (bHLH) oncogene SCL/tal undergoes frequent rearrangements activating ectopic expression. Despite the compelling epidemiological association of SCL/tal expression with T-ALL, no specific transforming function has been attributable to the protein product. However, investigators have recently demonstrated that forced overexpression of SCL/tal can block monocytic differentiation of M1 murine myeloid leukemia cells. Thus, inappropriate expression of wild-type SCL/tal protein may in part account for the maturation arrest phenotype observed in T-ALL cells. In this study, ectopic expression of the SCL/tal gene blocked the differentiation of C2C12 muscle precursor cells. Characterization of the mechanism of differentiation blockade showed that the SCL/tal protein repressed transcriptional activation by the myogenic bHLH factor MyoD. Protein interaction analysis showed that SCL/tal and MyoD compete for common partners (E bHLH proteins) but do not directly bind one other. A model is thus proposed in which ectopic SCL/tal protein, by its ability to titrate out E proteins, prevents the formation of bHLH complexes that drive cellular differentiation: the "Id-like" mechanism.
Goldfarb
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Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106-4943.
Lewandowska
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D016475:3T3 Cells; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D015329:Gene Rearrangement, T-Lymphocyte; D005813:Genes, Synthetic; D018257:Helix-Loop-Helix Motifs / Q000502:physiology*; D007942:Leukemia, Experimental / Q000473:pathology; D007951:Leukemia, Myeloid / Q000473:pathology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D009132:Muscles / Q000166:cytology; D017570:MyoD Protein / Q000037:antagonists & inhibitors / Q000737:chemistry; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009419:Nerve Tissue Proteins; D015202:Protein Engineering; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000737:chemistry; D000073940:Transcription Factor 4; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D017570:MyoD Protein; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D051820:TCF Transcription Factors; D015534:Trans-Activators; D000073940:Transcription Factor 4; D014157:Transcription Factors; C489366:Tal1 protein, mouse; C090743:Tcf4 protein, mouse