Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy.
Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy.
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DOI：
10.1038/nature07284
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发表时间：
2008-10-30
期刊：
影响因子：
64.8
通讯作者：
Cleary, Michael L.
中科院分区：
文献类型：
--
作者：
Wang, Zhong;Smith, Kevin S.;Murphy, Mark;Piloto, Obdulio;Somervaille, Tim C. P.;Cleary, Michael L.
糖原合成酶激酶3（GSK 3）是一种多功能丝氨酸/苏氨酸激酶，其参与多种生理过程中涉及的多种信号传导途径。这些途径中的几种与疾病发病机制有关，这促使人们努力开发用于治疗应用的GSK 3特异性抑制剂。然而，在此之前，在恶性肿瘤中靶向GSK 3并没有强有力的理由。在这里，我们报告的药理学，生理学和遗传学研究表明，在维持一个特定的亚型预后不良的人白血病，遗传定义的MLL原癌基因突变的致癌要求GSK 3。与其先前在抑制肿瘤相关信号通路中的特征性作用相反，GSK 3矛盾地通过最终涉及细胞周期蛋白依赖性激酶抑制剂p27 Kip 1的不稳定的机制支持MLL白血病细胞增殖和转化。在MLL白血病的临床前小鼠模型中抑制GSK 3提供了有希望的疗效证据，并将GSK 3标记为候选癌症药物靶标。
Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine kinase that participates in numerous signalling pathways involved in diverse physiological processes. Several of these pathways are implicated in disease pathogenesis, which has prompted efforts to develop GSK3-specific inhibitors for therapeutic applications. However, before now, there has been no strong rationale for targeting GSK3 in malignancies. Here we report pharmacological, physiological and genetic studies that demonstrate an oncogenic requirement for GSK3 in the maintenance of a specific subtype of poor prognosis human leukaemia, genetically defined by mutations of the MLL proto-oncogene. In contrast to its previously characterized roles in suppression of neoplasia-associated signalling pathways, GSK3 paradoxically supports MLL leukaemia cell proliferation and transformation by a mechanism that ultimately involves destabilization of the cyclin-dependent kinase inhibitor p27Kip1. Inhibition of GSK3 in a preclinical murine model of MLL leukaemia provides promising evidence of efficacy and earmarks GSK3 as a candidate cancer drug target.
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影响因子：
64.8
作者：
Jia, JH;Amanal, K;Jiang, J
通讯作者：
Jiang, J
影响因子：
16
作者：
Hughes, CM;Rozenblatt-Rosen, O;Meyerson, M
通讯作者：
Meyerson, M
DOI：
10.1073/pnas.0408836102
发表时间：
2005-01-18
影响因子：
11.1
作者：
Milne, TA;Hughes, CM;Hess, JL
通讯作者：
Hess, JL
影响因子：
8
作者：
Smith, KS;Jacobs, Y;Cleary, ML
通讯作者：
Cleary, ML
影响因子：
64.8
作者：
CROSS, DAE;ALESSI, DR;HEMMINGS, BA
通讯作者：
HEMMINGS, BA