Regulation of cell surface protease receptor S100A10 by retinoic acid therapy in acute promyelocytic leukemia (APL)
Regulation of cell surface protease receptor S100A10 by retinoic acid therapy in acute promyelocytic leukemia (APL)
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DOI：
10.1038/s41419-018-0954-6
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发表时间：
2018-09-11
影响因子：
9
通讯作者：
Waisman, David M.
中科院分区：
文献类型：
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作者：
Holloway, Ryan W.;Thomas, Margaret L.;Waisman, David M.
S100 A10（p11）是小的二聚EF-手型Ca 2+结合蛋白S100家族的成员，在多种细胞内和细胞外过程中发挥作用。以前的研究表明，p11本质上是不稳定的，需要结合膜联蛋白A2（p36），以防止其快速泛素化和降解。我们的实验室已经表明，p11水平是由癌蛋白PML/RAR α的表达刺激的。此外，用全反式维甲酸（ATRA）处理APL细胞系NB 4导致p36和p11蛋白的快速丢失。然而，ATRA调节p11水平的机制尚未建立。在这里，我们发现，蛋白酶体抑制剂，lactacystin逆转ATRA依赖的损失p11，但没有引起积累的泛素化形式的p11，这表明ATRA促进蛋白酶体降解p11在一个不依赖于泛素的方式。ATRA治疗MCF-7乳腺癌细胞减少p11，但不是p36转录和蛋白质水平，从而表明ATRA可以调节p11水平的PML/RAR α和p36独立。p36的过表达上调p11蛋白，但不上调mRNA水平，表明p36影响p11的表达后。泛素和p11在293 T细胞中的强制表达导致p11的泛素化，其被赖氨酸57的诱变所阻断。这项研究强调了类维生素A信号对p11的复杂调控，并挑战了泛素介导的p11蛋白酶体降解代表这种蛋白质调控的普遍机制的假设。
S100A10 (p11), a member of the S100 family of small dimeric EF-hand-type Ca2+-binding proteins, plays a role in a variety of both intracellular and extracellular processes. Previous studies have suggested that p11 is intrinsically unstable and requires binding to annexin A2 (p36) to prevent its rapid ubiquitylation and degradation. Our laboratory has shown that p11 levels are stimulated by the expression of the oncoprotein, PML/RAR alpha. Furthermore, treatment of the APL cell line, NB4 with all-trans retinoic acid (ATRA) causes the rapid loss of p36 and p11 protein. However, the mechanism by which ATRA regulates p11 levels has not been established. Here, we show that the proteasomal inhibitor, lactacystin reversed the ATRA-dependent loss of p11, but did not cause an accumulation of ubiquitylated forms of p11, suggesting that ATRA promotes the proteasomal degradation of p11 in an ubiquitin-independent manner. ATRA treatment of MCF-7 breast cancer cells reduced p11 but not p36 transcript and protein levels, thus indicating that ATRA can regulate p11 levels independently of PML/RAR alpha and p36. Overexpression of p36 upregulated p11 protein but not mRNA levels, indicating that p36 affects p11 post translationally. The forced expression of ubiquitin and p11 in 293 T cells resulted in ubiquitylation of p11 that was blocked by mutagenesis of lysine 57. This study highlights the complex regulation of p11 by retinoid signaling and challenges the hypothesis that ubiquitin-mediated proteasomal degradation of p11 represents a universal mechanism of regulation of this protein.