Induction of cyclooxygenase-2 by the activated MEKK1→SEK1/MKK4→p38 mitogen-activated protein kinase pathway
Induction of cyclooxygenase-2 by the activated MEKK1→SEK1/MKK4→p38 mitogen-activated protein kinase pathway
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DOI：
10.1074/jbc.273.21.12901
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发表时间：
1998-05-22
影响因子：
4.8
通讯作者：
Morrison, AR
中科院分区：
文献类型：
--
作者：
Guan, ZH;Buckman, SY;Morrison, AR
丝裂原活化蛋白激酶（MAPK）级联被认为是前列腺素生物合成的重要调节因子，之前我们报道过白细胞介素-1 β诱导JNK/SAPK和p38 MAPK的激活，同时上调环氧化酶(Cox)-2的表达和前列腺素E-2 （PGE(2)）的合成。我们的实验表明，Delta MEKK1（一种含有324个氨基酸的MEKK1的组成活性截断突变体）的过表达增加了Cox-2的表达和PGE(2)的产生，PGE(2)的产生被p38 MAPK的药理学抑制剂SC68376完全阻断。Delta MEKK1过表达导致c Jun n末端激酶/细胞外信号调节激酶（JNK/SAPK）和p38 MAPK的激活。此外，Delta MEKK1的激活增加了SEK1/MKK4的活性，而不是MKK3或MKK6的活性。这些发现表明，MEKK1—> SEK1/MKK4可能是一种上游激酶，能够激活p38 MAPK和JNK/SAPK，随后诱导Cox-2表达和PGE(2)的产生。我们还发现，过表达构成活性形式的SEK1 （SEK1- ed）会增加p38 MAPK和JNK/SAPK的磷酸化，并增加PGE(2)的产生和Cox-2的表达。相比之下，SEK1显性阴性形式（SEK1- al）的过表达降低了p38 MAPK和JNK/SAPK的磷酸化，并降低了Cox-2的表达。总之，这些数据表明MEKK1—> SEK1/MKK4—> p38 MAPK—>—> Cox-2级联连接MAPK通路成员与前列腺素生物合成的潜在作用。
The mitogen-activated protein kinase (MAPK) cascade is believed to function as an important regulator of prostaglandin biosynthesis, Previously we reported that interleukin-1 beta induces activation of JNK/SAPK and p38 MAPK with concomitant up-regulation of cyclooxygenase (Cox)-2 expression and prostaglandin E-2 (PGE(2)) synthesis. Our experiments demonstrate that overexpression of Delta MEKK1 (a constitutively active truncation mutant of MEKK1 containing the C-terminal 324 amino acids) increases Cox-2 expression and PGE(2) production which is completely blocked by SC68376, a pharmacologic inhibitor of p38 MAPK. Delta MEKK1 overexpression results in activation of both c Jun N-terminal kinases/extracellular signal-regulated kinases (JNK/SAPK) and p38 MAPK. Furthermore, activation of Delta MEKK1 increases SEK1/MKK4 but not MKK3 or MKK6 activity. These findings suggest that MEKK1 --> SEK1/MKK4 may function as an upstream kinase capable of activating both p38 MAPK and JNK/SAPK with subsequent induction of Cox-2 expression and PGE(2) production. We also found that overexpression of the constitutively active form of SEK1 (SEK1-ED) increases both p38 MAPK and JNK/SAPK phosphorylation, and increases PGE(2) production and Cox-2 expression. By comparison, overexpression of the dominant negative form of SEK1 (SEK1-AL) decreases the phosphorylation of both p38 MAPK and JNK/SAPK and reduces Cox-2 expression. Together, this data suggests a potential role for the MEKK1 --> SEK1/MKK4 --> p38 MAPK -->--> Cox-2 cascade linking members of the MAPK pathway with prostaglandin biosynthesis.