Novel role for JNK as a stress-activated Bcl2 kinase
Novel role for JNK as a stress-activated Bcl2 kinase
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DOI：
10.1074/jbc.m100279200
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发表时间：
2001-06-29
影响因子：
4.8
通讯作者：
May, WS
中科院分区：
文献类型：
--
作者：
Deng, XM;Xiao, L;May, WS
白细胞介素(IL)-3诱导的Bcl2丝氨酸（70）磷酸化可能需要其充分和有效的抗凋亡活性。然而，在缺乏IL-3的情况下，Bcl2表达的增加也可以延长细胞存活时间。为了确定IL-3停用后Bcl2如何在功能上磷酸化，研究人员寻找了一种应激激活的Bcl2激酶（SAK）。结果表明，anisomycin是应激激酶JNK/SAPK的有效激活剂，可以诱导Bcl2在Ser70位点磷酸化，并且JNK1可以在IL-3退出后被潜在激活，介导Bcl2磷酸化。JNK1在体外直接磷酸化Bc12，与Bc12共定位，并与Bcl-2协同介导在缺乏IL-3或各种应激作用下延长细胞存活。显性阴性(DN)-JNK1可以阻断大霉素和潜在IL-3戒断诱导的Bc12磷酸化（> 90%），并有效促进细胞死亡。此外，低剂量冈田酸（OA）是一种有效的蛋白磷酸酶1和2A抑制剂，可以激活mito原激活的蛋白激酶JNK1和ERK1/2，而不是p38激酶，诱导Bcl2磷酸化，延长因子剥夺细胞的细胞存活。由于PD98059是一种特异性MEK抑制剂，只能部分抑制OA诱导的Bc12磷酸化，但在表达DN-JNK1的细胞中完全阻断OA诱导的Bc12磷酸化，这支持了OA可能通过JNK1和ERK1/2共同参与的机制刺激Bc12磷酸化的结论。总的来说，这些发现表明JNK1作为SAK的新作用，并且可以至少部分解释在缺乏生长因子的情况下Bc12的功能性磷酸化是如何发生的。
Interleukin (IL)-3-induced Bcl2 phosphorylation at Ser(70) may be required for its full and potent antiapoptotic activity. However, in the absence of IL-3, increased expression of Bcl2 can also prolong cell survival. To determine how Bcl2 may be functionally phosphorylated following IL-3 withdrawal, a stress-activated Bcl2 kinase (SAK) was sought. Results indicate that anisomycin, a potent activator of the stress kinase JNK/SAPK, can induce Bcl2 phosphorylation at Ser70 and that JNK1 can be latently activated following IL-3 withdrawal to mediate Bcl2 phosphorylation. JNK1 directly phosphorylates Bc12 in vitro, co-localizes with Bc12, and collaborates with Bcl-2 to mediate prolonged cell survival in the absence of IL-3 or following various stress applications. Dominant-negative (DN)-JNK1 can block both anisomycin and latent IL-3 withdrawal-induced Bc12 phosphorylation (> 90%) and potently enhances cell death. Furthermore, low dose okadaic acid (OA), a potent protein phosphatase 1 and 2A inhibitor, can activate the mito gen-activated protein kinases JNK1 and ERK1/2, but not p38 kinase, to induce Bcl2 phosphorylation and prolong cell survival in factor-deprived cells. Since PD98059, a specific MEK inhibitor, can only partially inhibit OA-induced Bc12 phosphorylation but completely blocks OA-induced Bc12 phosphorylation in cells expressing DN-JNK1, this supports the conclusion that OA may stimulate Bc12 phosphorylation via a mechanism involving both JNK1 and ERK1/2. Collectively, these findings indicate a novel role for JNK1 as a SAK, and may explain, at least in part, how functional phosphorylation of Bc12 can occur in the absence of growth factor.