Abstract
TAL1/SCL is a basic helix-loop-helix (bHLH) oncoprotein that is expressed in several cell lines including many hematolymphoid cells, but not in T- and B-lineage cells. The TAL1 gene was originally discovered as being transcriptionally activated by chromosomal rearrangements in T-cell acute lymphoblastic leukemia (T-ALL). Here we have shown that TAL1 and the ubiquitously expressed murine bHLH transcription factor ALF1 formed heterodimers that, compared with ALF1 homodimers, had a more restricted E-box specificity and bound preferentially to the glucocorticoid-responsive E-box (Egre) motif (AACAGATGGT). Overexpression of the dominant inhibitory HLH protein Id1 in NIH3T3 cells reduced the transcriptional activity mediated by ALF1 homodimers, whereas the transcriptional activity mediated by TAL1/ALF1 heterodimers was resistant to Id overexpression. Our results show that ALF1 may serve as a dimerization partner for the bHLH oncoprotein TAL1 and form a complex with a distinctive DNA binding property. These findings support the hypothesis that the leukemic characteristics of the TAL1 oncoprotein could be mediated by activation of a set of target genes as heterodimeric complexes with ubiquitously expressed bHLH transcription factors such as ALF1 and that a principal role of TAL1 might be to neutralize an Id-mediated inactivation.
Highlights
The TAL1 gene is found transcriptionally activated in 25% of T-cell acute lymphoblastic leukemia (T-ALL)1 by tumor-specific rearrangements such as chromosomal translocations or local DNA recombinations [1,2,3]
Until now candidate genes regulated by the TAL1/class A basic helix-loop-helix (bHLH) heterodimer have not been identified in either T-cell acute lymphoblastic leukemia or hematopoietic lineages normally expressing TAL1
We show that the class A bHLH protein ALF1 and the class B bHLH protein TAL1 interact both in vitro and in vivo
Summary
The TAL1 gene ( abbreviated SCL or TCL5) is found transcriptionally activated in 25% of T-cell acute lymphoblastic leukemia (T-ALL) by tumor-specific rearrangements such as chromosomal translocations or local DNA recombinations [1,2,3]. The TAL1 gene codes for the full-length protein p42TAL1 of 331 amino acids and a truncated species p22TAL1 (amino acid residues 176 –331) lacking the transcriptional transactivation domain [15]. Both TAL1 versions include a dimerization and DNA-binding domain of the basic helix-loop-helix (bHLH) type [16]. As well as with TAL1, class A bHLH proteins can form heterodimers with helix-loop-helix proteins, Id proteins, which lack the basic domain required for DNA binding and prevent DNA binding of the complex (26 –29). In the context of Id protein, TAL1/E2A is a significantly better transcription activator than the E2A homodimer, due to a higher stability of the TAL1/E2A complex [30]
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