Retinoic acid-induced blr1 expression requires RARα, RXR, and MAPK activation and uses ERK2 but not JNK/SAPK to accelerate cell differentiation
Retinoic acid-induced blr1 expression requires RARα, RXR, and MAPK activation and uses ERK2 but not JNK/SAPK to accelerate cell differentiation
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DOI：
10.1078/0171-9335-00141
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发表时间：
2001-01-01
影响因子：
6.6
通讯作者：
Yen, A
中科院分区：
文献类型：
--
作者：
Battle, TE;Roberson, MS;Yen, A
人髓系白血病细胞系中视黄酸 (RA) 诱导的 blr1 表达的上游信号传导需求和 blr1 过表达的下游信号传导结果表明丝裂原激活蛋白激酶 (MAPK) 信号传导复合物参与这两种途径。已知 RA 诱导的 HL-60 细胞的骨髓分化和 G(1)/G(0) 生长停滞需要激活 RAR α 和 RXR 类视黄醇受体，以及激活 MAPK、ERK2。 Burkitt 淋巴瘤受体 1 (blr1) 基因的转录激活发生在 RA 诱导的 HL-60 细胞分化过程的早期，并且需要这三个相同的激活过程。使用激活 RAR α 或 RXR 类视黄醇受体的类视黄醇配体表明，只有当 RAR α 和 RXR 都被激活时，才能检测到 blr1 mRNA 的诱导。单独的 RAR α 和 RXR 选择性配体均不会诱导 blr1 的表达，但两种配体的组合诱导 blr1 的表达程度与 RA 相同。 MAPKK (MEK) 抑制剂 PD98059 用于确定细胞外信号调节激酶 (ERK2) 激活是否是诱导 blr1 mRNA 所必需的，由于 RA 或激活的 RAR α 加 RXR 配体，PD98059 抑制诱导的 blr1 mRNA 表达，表明 ERK2 激活对于 blr1 mRNA 表达是必需的。先前的研究表明，blr1 的异位表达也会导致 MAPK 激活增加，特别是 ERK2，并随后加速 RA 诱导的分化和 G(1)/G(0) 生长停滞。抑制 ERK2 激活会抑制 blr1 转染子的分化，表明加速分化反映了 blr1 增强的 ERK2 激活。目前的数据还表明，blr1 的异位表达增加了 JNK/SAPK 活性，但加速 RA 诱导的分化和生长停滞不需要 JNK/SAPK 激活。结果表明，已知 HL-60 分化所需的信号、激活的 RAR α、RXR 和 ERK2 是 blr1 mRNA 表达所必需的。 blr1 过度表达的下游后果包括增强 MAPK 信号传导。
Upstream signaling requirements of retinoic acid (RA)induced blr1 expression and downstream signaling consequences of blr1 over-expression in a human myeloid leukemia cell line demonstrate that mitogen-activated protein kinase (MAPK) signaling complexes are involved in both avenues. RA-induced myeloid differentiation and G(1)/G(0) growth arrest of HL-60 cells is known to require the activation of the RAR alpha and RXR retinoid receptors, as well as activation of the MAPK, ERK2. Transcriptional activation of the Burkitt's lymphoma receptor 1 (blr1) gene occurs early during RA-induced differentiation of HL-60 cells and requires these same three activating processes. The use of retinoid ligands that activate either the RAR alpha or the RXR retinoid receptors revealed that blr1 mRNA induction was detectable only when both RAR alpha and RXR were activated. Neither the RAR alpha nor RXR selective ligands alone induced expression of blr1, but the combination of the two ligands induced the expression of blr1 to the same extent as RA. The MAPKK (MEK) inhibitor, PD98059, was used to determine whether extracellular signal-regulated kinase (ERK2) activation was necessary for induction of blr1 mRNA, PD98059 inhibited induced blr1 mRNA expression, due to RA or activated RAR alpha plus RXR ligands, indicating that ERK2 activation is necessary for blr1 mRNA expression. Previous studies showed that ectopic expression of blr1 also caused increased MAPK activation, in particular ERK2, and subsequently accelerated RA-induced differentiation and G(1)/G(0) growth arrest. Inhibition of ERK2 activation inhibited differentiation of blr1 transfectants, suggesting that the accelerated differentiation reflected blr1-enhanced ERK2 activation. The present data also demonstrate that ectopic expression of blr1 increased JNK/SAPK activity, but JNK/SAPK activation was not needed for accelerated RA-induced differentiation and growth arrest. The results show that the signals known to be required for HL-60 differentiation, activated RAR alpha, RXR, and ERK2, are necessary for blr1 mRNA expression. Downstream consequences of blr1 overexpression include enhanced MAPK signaling.