Phosphorylation by mitogen-activated protein kinase mediates the hypoxia-induced turnover of the TAL1/SCL transcription factor in endothelial cells.
Phosphorylation by mitogen-activated protein kinase mediates the hypoxia-induced turnover of the TAL1/SCL transcription factor in endothelial cells.
复制标题
丝裂原激活蛋白激酶的磷酸化介导内皮细胞中缺氧诱导的 TAL1/SCL 转录因子的更新。
DOI：
10.1074/jbc.m109812200
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Brandt,StephenJ
中科院分区：
文献类型：
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作者：
Tang,Tong;Arbiser,JackL;Brandt,StephenJ
碱性螺旋-环-螺旋转录因子 TAL1（或 SCL）最初是通过参与 T 细胞急性淋巴细胞白血病的染色体重排而发现的，是造血发育所必需的。 TAL1 在胚胎血管重塑中也发挥着关键作用，并在出生后在内皮细胞中表达，尽管人们对其在这种细胞类型中的功能或调节知之甚少。我们在此报告，重要的促血管生成刺激缺氧会刺激内皮细胞中 TAL1 的磷酸化、泛素化和蛋白酶体分解。胰蛋白酶磷酸肽图谱和化学抑制剂研究表明，缺氧诱导了丝裂原激活蛋白激酶介导的蛋白质中单个丝氨酸残基 Ser122 的磷酸化，定点诱变证明 Ser122 磷酸化对于永生化鼠内皮细胞系中 TAL1 周转的缺氧加速是必要的。最后，虽然在大血管和小血管的内皮细胞中均检测到 TAL1 表达，但仅在微血管内皮细胞中观察到缺氧诱导的 TAL1 更新。除了对血管生成过程中 TAL1 功能的影响外，这些结果还表明，对有丝分裂信号传导重要的蛋白激酶也可在缺氧内皮细胞中用于靶向转录因子进行破坏。
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, Ser122, in the protein, and site-directed mutagenesis demonstrated that Ser122phosphorylation 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.