Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS One. 2010 Sep 10;5(9):e12692. doi: 10.1371/journal.pone.0012692.
The Lymphoblastic leukemia 1 (LYL1) gene is a proto-oncogenic transcription factor found upregulated in patients with T-cell acute lymphoblastic leukemia (T-cell ALL). Initially, the upregulation was described to be as a result of a translocation. However, further studies revealed that transcriptional upregulation of LYL1could also occur without translocations. In addition, post-translational mechanisms, such as protein degradation could influence LYL1 expression as well.
METHODOLOGY/PRINCIPAL FINDINGS: In this study, we considered possible post-translational regulation of Lyl1, and investigated fundamental mechanisms governing LYL1 degradation in cell-based culture assays. We identify a PEST sequence motif located in the N-terminus of LYL1, which determines the efficiency of LYL1 degradation by the proteasome. The absence of the PEST degradation site leads to accumulation or upregulation of LYL1. We also show that LYL1 is phosphorylated by MAPK at S36, and determined that proteasomal degradation of LYL1 occurs in a phosphorylation-independent manner.
CONCLUSIONS/SIGNIFICANCE: Understanding LYL1 degradation is a step forward not only towards deciphering the normal function and regulation of LYL1, but could suggest post-translational mechanisms for upregulation of LYL1 that may contribute to its oncogenic role.
淋巴母细胞白血病 1（LYL1）基因是一种原癌转录因子，在 T 细胞急性淋巴细胞白血病（T 细胞 ALL）患者中上调。最初，上调被描述为易位的结果。然而，进一步的研究表明，LYL1 的转录上调也可能在没有易位的情况下发生。此外，翻译后机制，如蛋白质降解，也可能影响 LYL1 的表达。
方法/主要发现：在这项研究中，我们考虑了 Lyl1 可能的翻译后调节，并在基于细胞的培养测定中研究了控制 LYL1 降解的基本机制。我们确定了 LYL1 N 端的一个 PEST 序列基序，该基序决定了 LYL1 被蛋白酶体降解的效率。PEST 降解位点的缺失导致 LYL1 的积累或上调。我们还表明，LYL1 被 MAPK 在 S36 处磷酸化，并确定 LYL1 的蛋白酶体降解以非磷酸化依赖的方式发生。
结论/意义：理解 LYL1 的降解不仅是朝着破译 LYL1 的正常功能和调节迈出的一步，而且可能提示 LYL1 上调的翻译后机制，这可能有助于其致癌作用。
