Mechanisms of bcr-Abl-mediated NF-κB/Re1 activation
Mechanisms of bcr-Abl-mediated NF-κB/Re1 activation
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DOI：
10.1016/s0301-472x(03)00069-9
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发表时间：
2003-06-01
影响因子：
2.6
通讯作者：
Munzert, G
中科院分区：
文献类型：
--
作者：
Kirchner, D;Duyster, J;Munzert, G
Bcr-Abl构成一种失调的酪氨酸激酶，参与慢性髓性白血病（CML）和急性淋巴细胞白血病（ALL）的发病机制。虽然转录因子NF-kappaB/Rel的激活已被证实，但Bcr-Abl激活NF-kappaB/Rel的机制仍不清楚。本文首次证实了Bcr-Abl和v-Abl对NF-kappaB/Rel的激活作用。此外，我们还研究了Bcr-Abl和v-Abl诱导NF-kappaB/Rel的机制。Bcr-Abl和v-Abl均诱导Ba/F3细胞NF-kappaB/Rel DNA结合。DNA结合是p65/RelA核易位的结果，而p65/RelA的表达不受影响。p65/RelA的核易位至少部分是由于ikapabα降解增加，而ikapabα降解与IKK激酶（IKK）活性无关。Bcr-Abl和v-Abl不解除IKK活性的调控。NF-kappaB/Rel转激活依赖于abl激酶活性，但不依赖于Grb2和Grb10与bcr序列的结合。此外，NF-kappaB/Rel的激活依赖于Ras活性。原代CML细胞显示组成型p65/RelA NF-kappaB/Rel DNA结合活性。因此，NF-kappaB/Rel代表了CML分子治疗的潜在靶点。(C) 2003国际实验血液学学会。Elsevier Inc.出版。
Bcr-Abl constitutes a deregulated tyrosine kinase involved in the pathogenesis of chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL). Although activation of the transcription factor NF-kappaB/Rel has been demonstrated, mechanisms of NF-kappaB/Rel activation by Bcr-Abl remain obscure. In this paper we demonstrate activation of NF-kappaB/Rel by Bcr-Abl and for the first time by v-Abl. Furthermore, we investigated mechanisms of NF-kappaB/Rel induction by Bcr-Abl and v-Abl. Both Bcr-Abl and v-Abl induced NF-kappaB/Rel DNA binding in Ba/F3 cells. DNA binding was a result of nuclear translocation of p65/RelA, whereas p65/RelA expression was unaffected. Nuclear translocation of p65/RelA is at least partially due to increased IkappaBalpha degradation, which is independent of IkappaB kinase (IKK) activity. IKK activity is not deregulated by Bcr-Abl and v-Abl. NF-kappaB/Rel transactivation was dependent on abl kinase activity but independent of Grb2 and Grb10 binding to bcr sequences. In addition, NF-kappaB/Rel activation was dependent on Ras activity. Primary CML blasts showed constitutive p65/RelA NF-kappaB/Rel DNA binding activity. Thus NF-kappaB/Rel represents a potential target for molecular therapies in CML. (C) 2003 International Society for Experimental Hematology. Published by Elsevier Inc.