絲氨酸/蘇氨酸蛋白激酶GSK-3（糖原合成酶激酶-3）是很多信號(hào)通道的構(gòu)成部分，包括那些在糖原生產(chǎn),、細(xì)胞凋亡和干細(xì)胞維持中所涉及的信號(hào)通道,。這些通道中的其中一些已被與人類疾病聯(lián)系在一起,，而GSK-3抑制劑則被看作是糖尿病和阿爾茨海默氏癥的可能治療藥物。
現(xiàn)在,，GSK-3被發(fā)現(xiàn)在支持急性白血病的病情發(fā)展中扮演一個(gè)以前人們未曾料到的角色——這個(gè)角色與人們根據(jù)其在抑制某些癌癥中被異常激發(fā)的信號(hào)通道中扮演的已知角色所做出的預(yù)測是相反的,。比較矛盾的是，GSK-3支持由MLL（混合型白血?。┲掳┗蛞鸬囊环N與眾不同的遺傳性白血病亞型,。在一個(gè)MLL白血病的小鼠模型中，GSK-3的抑制影響癌癥病情的發(fā)展,，說明它的確是一個(gè)候選藥物作用目標(biāo),。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature 455, 1205-1209 (30 October 2008) | doi:10.1038/nature07284
Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy
Zhong Wang1, Kevin S. Smith1, Mark Murphy1, Obdulio Piloto1, Tim C. P. Somervaille1 & Michael L. Cleary1
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA
Abstract
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.
