Korus Malgorzata, Mahon Gwendolyn M, Cheng Li, Whitehead Ian P
Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, Newark, New Jersey, NJ 07103, USA.
Oncogene. 2002 Jul 11;21(30):4601-12. doi: 10.1038/sj.onc.1205678.
The oncogenic fusion protein p210 Bcr-Abl is causally associated with virtually all cases of chronic myelogenous leukemia. The wild-type Bcr product has several recognizable structural and functional motifs including a domain that contains guanine nucleotide exchange activity for Rho family GTPases (DH/PH domain). Although this domain is retained within p210 Bcr-Abl, it has no known signaling activities in vivo. Here we report that a fragment of Bcr that encodes the isolated DH/PH domain is a potent activator of the NF-kappaB transcription factor. Within the context of full length Bcr, this activity is regulated by proximal flanking sequences that suppress the DH/PH domain encoded guanine nucleotide exchange activity. NF-kappaB activation by Bcr is not mediated by nuclear translocation, but rather by p38 mitogen-activated protein kinase (MAPK)-dependent modification of the RelA/p65 transactivation domain. Although we were able to demonstrate that Bcr can function as an exchange factor for Cdc42 in vivo, NF-kappaB activation appears to occur via a Cdc42-independent mechanism. These studies constitute direct evidence that the Bcr RhoGEF domain can function in vivo, and identify a new signaling activity that may contribute to the transforming potential of p210 Bcr-Abl.
致癌融合蛋白p210 Bcr-Abl实际上与所有慢性粒细胞白血病病例都存在因果关联。野生型Bcr产物具有几个可识别的结构和功能基序，包括一个含有对Rho家族GTP酶具有鸟嘌呤核苷酸交换活性的结构域（DH/PH结构域）。尽管该结构域保留在p210 Bcr-Abl中，但在体内尚无已知的信号传导活性。在此我们报告，编码分离的DH/PH结构域的Bcr片段是NF-κB转录因子的有效激活剂。在全长Bcr的背景下，该活性受抑制DH/PH结构域编码的鸟嘌呤核苷酸交换活性的近端侧翼序列调控。Bcr对NF-κB的激活不是通过核转位介导的，而是通过p38丝裂原活化蛋白激酶（MAPK）依赖的RelA/p65反式激活结构域修饰来实现。尽管我们能够证明Bcr在体内可作为Cdc42的交换因子发挥作用，但NF-κB的激活似乎是通过一种不依赖Cdc42的机制发生的。这些研究构成了Bcr RhoGEF结构域在体内可发挥功能的直接证据，并确定了一种可能有助于p210 Bcr-Abl转化潜能的新信号传导活性。
