Phosphorylation by mitogen-activated protein kinase mediates the hypoxia-induced turnover of the TAL1/SCL transcription factor in endothelial cells.
The basic helix-loop-helix transcription factor TAL1 (or SCL), originally identified from its involvement by a chromosomal rearrangement in T-cell acute lymphoblastic leukemia, is required for hematopoietic development. TAL1 also has a critical role in embryonic vascular remodeling and is expressed in endothelial cells postnatally, although little is known about its function or regulation in this cell type. We report here that the important proangiogenic stimulus hypoxia stimulates phosphorylation, ubiquitination, and proteasomal breakdown of TAL1 in endothelial cells. Tryptic phosphopeptide mapping and chemical inhibitor studies showed that hypoxia induced the mitogen-activated protein kinase-mediated phosphorylation of a single serine residue, Ser(122), in the protein, and site-directed mutagenesis demonstrated that Ser(122) phosphorylation was necessary for hypoxic acceleration of TAL1 turnover in an immortalized murine endothelial cell line. Finally, whereas TAL1 expression was detected in endothelial cells from both large and small vessels, hypoxia-induced TAL1 turnover was observed only in microvascular endothelial cells. Besides their implications for TAL1 function in angiogenic processes, these results demonstrate that a protein kinase(s) important for mitogenic signaling is also utilized in hypoxic endothelial cells to target a transcription factor for destruction.
Tang
Tong
T
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Arbiser
Jack L
JL
Brandt
Stephen J
SJ
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002384:Catalysis; D015687:Cell Hypoxia; D002460:Cell Line; D002461:Cell Line, Transformed; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011518:Proto-Oncogene Proteins; D012694:Serine / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins; D020928:Mitogen-Activated Protein Kinases; D009097:Multienzyme Complexes; D046988:Proteasome Endopeptidase Complex; D011518:Proto-Oncogene Proteins; D012694:Serine; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C489366:Tal1 protein, mouse; C067143:TAL1 protein, human