The extracellular signal-regulated kinase pathway phosphorylates AML1, an acute myeloid leukemia gene product, and potentially regulates its transactivation ability
The extracellular signal-regulated kinase pathway phosphorylates AML1, an acute myeloid leukemia gene product, and potentially regulates its transactivation ability
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DOI：
10.1128/mcb.16.7.3967
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发表时间：
1996-07
影响因子：
5.3
通讯作者：
Tomoyuki Tanaka;M. Kurokawa;K. Ueki;Kozo Tanaka;Y. Imai;K. Mitani;K. Okazaki;N. Sagata;Y. Yaza
中科院分区：
文献类型：
--
作者：
Tomoyuki Tanaka;M. Kurokawa;K. Ueki;Kozo Tanaka;Y. Imai;K. Mitani;K. Okazaki;N. Sagata;Y. Yaza
AML1（也称为 PEBP2alphaB、CBFA2 或 CBFalpha2）是人类白血病染色体异常中最常被破坏的基因之一。据报道，AML1可能通过各种相关基因的转录调节在骨髓造血分化和其他生物现象中发挥关键作用。在这里，我们研究了通过信号转导途径调节 AML1 功能的机制。结果表明，AML1 在体内富含脯氨酸、丝氨酸和苏氨酸的区域内的两个丝氨酸残基上被磷酸化，依赖于细胞外信号调节激酶 (ERK) 的激活以及造血细胞系中白细胞介素 3 的刺激。 AML1 的这些体内磷酸化位点在体外被 ERK 直接磷酸化。尽管没有观察到野生型 AML1 和磷酸化位点突变体在 DNA 结合亲和力方面的差异，但我们已经证明 ERK 依赖性磷酸化增强了 AML1 的反式激活能力。此外，磷酸化位点突变降低了成纤维细胞中 AML1 的转化能力。这些数据表明 AML1 功能可能受到 ERK 的调节，而 ERK 是由细胞因子和生长因子刺激激活的。这项研究为阐明 AML1 功能调节机制的未明确方面提供了一些重要线索。
AML1 (also called PEBP2alphaB, CBFA2, or CBFalpha2) is one of the most frequently disrupted genes in chromosome abnormalities seen in human leukemias. It has been reported that AML1 plays several pivotal roles in myeloid hematopoietic differentiation and other biological phenomena, probably through the transcriptional regulation of various relevant genes. Here, we investigated the mechanism of regulation of AML1 functions through signal transduction pathways. The results showed that AML1 is phosphorylated in vivo on two serine residues within the proline-, serine-, and threonine-rich region, with dependence on the activation of extracellular signal-regulated kinase (ERK) and with interleukin-3 stimulation in a hematopoietic cell line. These in vivo phosphorylation sites of AML1 were phosphorylated directly in vitro by ERK. Although differences between wild-type AML1 and phosphorylation site mutants in DNA-binding affinity were not observed, we have shown that ERK-dependent phosphorylation potentiates the transactivation ability of AML1. Furthermore the phosphorylation site mutations reduced the transforming capacity of AML1 in fibroblast cells. These data indicate that AML1 functions are potentially regulated by ERK, which is activated by cytokine and growth factor stimuli. This study provides some important clues for clarifying unidentified facets of the regulatory mechanism of AML1 function.