Battle T E, Roberson M S, Zhang T, Varvayanis S, Yen A
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. traci
Eur J Cell Biol. 2001 Jan;80(1):59-67. doi: 10.1078/0171-9335-00141.
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 G1/G0 growth arrest of HL-60 cells is known to require the activation of the RARalpha 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 RARalpha or the RXR retinoid receptors revealed that blr1 mRNA induction was detectable only when both RARalpha and RXR were activated. Neither the RARalpha 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 RARalpha 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 G1/G0 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 RARalpha, RXR, and ERK2, are necessary for blr1 mRNA expression. Downstream consequences of blr1 overexpression include enhanced MAPK signaling.
视黄酸（RA）诱导blr1表达的上游信号要求以及blr1在人髓系白血病细胞系中过表达的下游信号后果表明，丝裂原活化蛋白激酶（MAPK）信号复合物参与了这两个途径。已知RA诱导HL-60细胞的髓系分化和G1/G0生长停滞需要RARα和RXR类视黄醇受体的激活，以及MAPK、ERK2的激活。在RA诱导HL-60细胞分化的早期阶段，伯基特淋巴瘤受体1（blr1）基因的转录激活就会发生，并且需要这三个相同的激活过程。使用激活RARα或RXR类视黄醇受体的类视黄醇配体表明，只有当RARα和RXR都被激活时，才能检测到blr1 mRNA的诱导。单独的RARα或RXR选择性配体均不能诱导blr1的表达，但两种配体的组合诱导blr1表达的程度与RA相同。MAPKK（MEK）抑制剂PD98059被用于确定细胞外信号调节激酶（ERK2）的激活对于blr1 mRNA的诱导是否必要。PD98059抑制了由RA或激活的RARα加RXR配体诱导的blr1 mRNA表达，表明ERK2激活对于blr1 mRNA表达是必要的。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，随后加速RA诱导的分化和G1/G0生长停滞。抑制ERK2激活会抑制blr1转染细胞的分化，这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并不需要JNK/SAPK激活。结果表明，已知HL-60分化所需的信号，即激活的RARα、RXR和ERK2，对于blr1 mRNA表达是必要的。blr1过表达的下游后果包括增强的MAPK信号传导。
