CREB in the pathophysiology of cancer: implications for targeting transcription factors for cancer therapy.
CREB in the pathophysiology of cancer: implications for targeting transcription factors for cancer therapy.
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DOI：
10.1158/1078-0432.ccr-08-1137
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发表时间：
2009-04-15
期刊：
影响因子：
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通讯作者：
Frank DA
中科院分区：
文献类型：
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作者：
Sakamoto KM;Frank DA
转录因子是细胞中基因表达模式的关键调节因子，并直接控制诸如增殖、存活、自我更新和侵袭的中心过程。鉴于这一关键作用，转录因子的功能通常受到密切调控，通常通过瞬时磷酸化。尽管转录因子通常不被癌细胞中的突变直接修饰，但它们经常通过影响“上游”途径的突变而被组成性激活。通过持续驱动关键靶基因的表达，这些致癌转录因子在肿瘤发病机制中发挥核心作用。一种这样的转录因子是cAMP调节元件结合蛋白（CREB），其可以通过许多激酶（包括Akt、p90 Rsk、蛋白激酶A和钙/钙调蛋白依赖性激酶）的磷酸化来激活，并调节其失调表达促进肿瘤发生的基因，包括细胞周期蛋白、Bcl-2家族成员和Egr-1。CREB在许多形式的人类癌症（包括急性髓性白血病（AML）和非小细胞肺癌）中过表达和组成性磷酸化，并且似乎在疾病发病机制和预后中起直接作用。虽然转录因子一直不是药物开发的中心焦点，但最近的进展表明CREB和其他此类蛋白质可能是癌症治疗的有价值的靶点。
Transcription factors are key regulators of the pattern of gene expression in a cell and directly control central processes such as proliferation, survival, self-renewal, and invasion. Given this critical role, the function of transcription factors is normally regulated closely, often through transient phosphorylation. Although transcription factors are not often directly modified by mutations in cancer cells, they frequently become activated constitutively through mutations affecting “upstream” pathways. By continually driving the expression of key target genes, these oncogenic transcription factors play a central role in tumor pathogenesis. One such transcription factor is the cAMP-regulatory element-binding protein (CREB), which can be activated through phosphorylation by a number of kinases, including Akt, p90Rsk, protein kinase A, and calcium/calmodulin-dependent kinases and regulates genes whose deregulated expression promotes oncogenesis, including cyclins, Bcl-2 family members, and Egr-1. CREB is overexpressed and constitutively phosphorylated in a number of forms of human cancer, including acute myeloid leukemia (AML) and non – small cell lung cancer, and appears to play a direct role in disease pathogenesis and prognosis. Although transcription factors have not been a central focus of drug development, recent advances suggest that CREB and other such proteins may be worthwhile targets for cancer therapy.