Oncogenic Activation of NF-κB
Oncogenic Activation of NF-κB
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DOI：
10.1101/cshperspect.a000109
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发表时间：
2010-06-01
影响因子：
7.2
通讯作者：
Staudt, Louis M.
中科院分区：
文献类型：
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作者：
Staudt, Louis M.
最近的遗传学证据已经确定了NF-κ B信号在癌症中的发病作用。当正常B淋巴细胞对抗原应答时，NF-κ B信号传导瞬时参与，但是源自这些细胞的淋巴瘤积累组成性激活NF-κ B信号传导的遗传病变。淋巴瘤中的许多遗传畸变改变了CARD 11、MALT 1或BCL 10，它们构成了B细胞受体和I κ B激酶之间的信号复合物。弥漫性大B细胞淋巴瘤的活化B细胞样亚型通过多种机制激活NF-κ B，包括CARD 11中的致癌突变和B细胞受体信号传导的慢性活性形式。正常浆细胞响应于骨髓微环境中的配体而激活NF-κ B，但其恶性对应物多发性骨髓瘤维持稳定激酶NIK的多种遗传命中，导致经典和替代NF-κ B途径的组成性激活。上皮癌中的各种致癌异常，包括突变的K-ras，参与非常规的Ik B激酶以激活NF-κ B。在这些癌症类型中的每一种中抑制组成性NF-κ B信号传导诱导细胞凋亡，为开发用于治疗癌症的NF-κ B途径抑制剂提供了理论基础。
Recent genetic evidence has established a pathogenetic role for NF-kappa B signaling in cancer. NF-kappa B signaling is engaged transiently when normal B lymphocytes respond to antigens, but lymphomas derived from these cells accumulate genetic lesions that constitutively activate NF-kappa B signaling. Many genetic aberrations in lymphomas alter CARD11, MALT1, or BCL10, which constitute a signaling complex that is intermediate between the B-cell receptor and I kappa B kinase. The activated B-cell-like subtype of diffuse large B-cell lymphoma activates NF-kappa B by a variety of mechanisms including oncogenic mutations in CARD11 and a chronic active form of B-cell receptor signaling. Normal plasma cells activate NF-kappa B in response to ligands in the bone marrow microenvironment, but their malignant counterpart, multiple myeloma, sustains a variety of genetic hits that stabilize the kinase NIK, leading to constitutive activation of the classical and alternative NF-kappa B pathways. Various oncogenic abnormalities in epithelial cancers, including mutant K-ras, engage unconventional IkB kinases to activate NF-kappa B. Inhibition of constitutive NF-kappa B signaling in each of these cancer types induces apoptosis, providing a rationale for the development of NF-kappa B pathway inhibitors for the treatment of cancer.