Tang Tong, Arbiser Jack L, Brandt Stephen J
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
J Biol Chem. 2002 May 24;277(21):18365-72. doi: 10.1074/jbc.M109812200. Epub 2002 Mar 19.
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.
基本螺旋-环-螺旋转录因子TAL1（或SCL）最初是从其因染色体重排参与T细胞急性淋巴细胞白血病中被鉴定出来的，它是造血发育所必需的。TAL1在胚胎血管重塑中也起关键作用，并且在出生后在内皮细胞中表达，尽管对其在这种细胞类型中的功能或调控知之甚少。我们在此报告，重要的促血管生成刺激因子缺氧会刺激内皮细胞中TAL1的磷酸化、泛素化和蛋白酶体降解。胰蛋白酶磷酸肽图谱分析和化学抑制剂研究表明，缺氧诱导该蛋白中单个丝氨酸残基Ser(122)的丝裂原活化蛋白激酶介导的磷酸化，定点诱变表明Ser(122)磷酸化对于永生化小鼠内皮细胞系中TAL1周转的缺氧加速是必需的。最后，虽然在大血管和小血管的内皮细胞中都检测到了TAL1的表达，但仅在微血管内皮细胞中观察到了缺氧诱导的TAL1周转。除了它们对TAL1在血管生成过程中的功能的影响外，这些结果表明，对有丝分裂信号传导重要的一种蛋白激酶也被缺氧内皮细胞用于靶向破坏一种转录因子。
