title: Target-dependent effect of phosphorylation on the DNA binding activity of the TAL1/SCL oncoprotein.
abstract: Activation of the TAL1 (or SCL) gene, initially identified through its involvement by a recurrent chromosomal translocation, is the most frequent gain-of-function mutation recognized in T-cell acute lymphoblastic leukemia. The translational products of this gene contain the basic domain helix-loop-helix motif characteristic of a family of transcription factors that bind to a consensus nucleotide sequence termed the E-box. Previous work established that the TAL1 proteins are phosphorylated exclusively on serine and identified Ser122 as a substrate for the mitogen-activated protein kinase ERK-1. We provide evidence that an additional serine residue, Ser172, located in a conserved region proximal to the DNA binding domain and sharing homology with a similarly positioned sequence in the HLH oncoprotein LYL1, can be phosphorylated in vitro and in vivo by the catalytic subunit of cAMP-dependent protein kinase. Phosphorylation was found to alter TAL1 DNA binding activity in a target-dependent manner that was influenced by both the specific CANNTG E-box core motif and its flanking sequences. In contrast, the ability of TAL1 to interact with the E2A gene product E12 and its subcellular localization in transfected COS cells were unaffected by Ser172 phosphorylation. These results suggest this serine residue has a regulatory function and indicate a mechanism by which phosphorylation could affect DNA binding site discrimination.
authors.affiliation: Department of Medicine,Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Prasad
authors.forename: S J
authors.initials: SJ
authors.lastname: Brandt
mesh_terms: D000409:Alanine / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001665:Binding Sites; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016296:Mutagenesis; D009363:Neoplasm Proteins / Q000235:genetics; D010748:Phosphopeptides / Q000032:analysis; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000409:Alanine; D051792:Basic Helix-Loop-Helix Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D004247:DNA; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D010748:Phosphopeptides; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D012694:Serine; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C490130:Lyl1 protein, mouse; C489366:Tal1 protein, mouse