Reduced O glycosylation of Sp1 is associated with increased proteasome susceptibility
Reduced O glycosylation of Sp1 is associated with increased proteasome susceptibility
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DOI：
10.1128/mcb.17.5.2550
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发表时间：
1997-05-01
影响因子：
5.3
通讯作者：
Kudlow, JE
中科院分区：
文献类型：
--
作者：
Han, I;Kudlow, JE
Sp1是一种广泛表达的转录因子，对于编码管家蛋白的TATA-少基因的调节特别重要。大多数生长因子和受体也由这些基因编码。Sp1通过单糖N-乙酰葡糖胺的共价键被多个O糖基化基于早期的观察，即在血管平滑肌细胞中，生长因子基因转录可以被葡萄糖和葡糖胺调节，我们确定了Sp1糖基化是否可以被调节，以及这种修饰是否改变了Sp1的功能，我们发现，当细胞暴露于5 mM葡萄糖胺时，Sp1变得高糖基化，而在葡萄糖饥饿下，用环AMP（cAMP）刺激导致该蛋白质几乎完全去糖基化，与这种低糖基化状态相关，Sp1被可被特异性蛋白酶体抑制剂lactacystin和LLnL抑制的酶快速蛋白水解降解，用葡萄糖或葡糖胺处理细胞保护Sp1免受cAMP介导的降解，而阻断葡糖胺合成消除了葡萄糖而不是葡糖胺保护，这种对Sp1的影响是特异性的，因为Stat-3和E2 F转录因子在这些条件下不会发生降解。Sp1的O-GlcNAc修饰可能起到营养检查点的作用，在缺乏足够营养的情况下，Sp1变得低糖基化，从而受到蛋白酶体降解。这一过程可能会导致一般转录减少，从而保存营养。
Sp1 is a ubiquitously expressed transcription factor that is particularly important for the regulation of TATA-less genes that encode housekeeping proteins. Most growth factors and receptors are also encoded by such genes. Sp1 is multiply O glycosylated by covalent linkage of the monosaccharide N-acetylglucosamine (O-GlcNAc) to serine and threonine residues, Based on an earlier observation that growth factor gene transcription can be regulated by glucose and glucosamine in vascular smooth muscle cells, we determined whether Sp1 glycosylation could be regulated and if this modification altered Sp1 function, We found that Sp1 becomes hyperglycosylated when cells are exposed to 5 mM glucosamine, whereas under glucose starvation, stimulation with cyclic AMP (cAMP) results in nearly complete deglycosylation of this protein, Correlating with this hypoglycosylated state, Sp1 is rapidly proteolytically degraded by an enzyme(s) that can be inhibited by specific proteasome inhibitors, lactacystin and LLnL, Treatment of cells with glucose or glucosamine protects Sp1 from cAMP-mediated degradation, whereas blockade of glucosamine synthesis abrogates glucose but not glucosamine protection, This effect on Sp1 is specific, in that the Stat-3 and E2F transcription factors did not undergo degradation under these conditions. The O-GlcNAc modification of Sp1 may play a role as a nutritional checkpoint, In the absence of adequate nutrition, Sp1 becomes hypoglycosylated and thereby subject to proteasome degradation. This process could potentially result in reduced general transcription, thereby conserving nutrients.