Class I PI3K in oncogenic cellular transformation.
Class I PI3K in oncogenic cellular transformation.
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DOI：
10.1038/onc.2008.244
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发表时间：
2008-09-18
期刊：
影响因子：
8
通讯作者：
Vogt, P. K.
中科院分区：
文献类型：
--
作者：
Zhao, L.;Vogt, P. K.
I类磷酸肌醇3-激酶（PI 3 K）是一种二聚体酶，由催化亚基和调节亚基组成。催化亚基以四种亚型存在，分别命名为p110α、p110β、p110γ和p110δ。这些联合收割机与几个调节亚基结合;对于p110α、β和δ，标准调节亚基是p85，对于p110γ，是p101。PI 3 K在人类癌症中发挥重要作用。PIK 3CA是编码p110α的基因，在乳腺癌、前列腺癌、结肠癌和子宫内膜癌等常见癌症中经常发生突变。这些突变中的80%由酶的螺旋或激酶结构域中的三个氨基酸取代之一表示。突变型p110α在酶和信号传导活性方面显示出功能的增加，并且在细胞培养物和动物模型系统中是致癌的。结构和遗传学数据表明，突变影响调节分子间和分子内的相互作用，并支持这样的结论，即至少有两种分子机制的功能获得在p110α。其中一种机制的运作在很大程度上独立于与p85的结合，另一种机制则取消了与Ras相互作用的要求。p110的非α亚型不显示癌症特异性突变。然而，它们通常在癌症中差异表达，与p110α相反，野生型p110的非α亚型在细胞培养中过表达时是致癌的。p110的异构体已成为有前途的药物靶点。异构体选择性抑制剂已被鉴定。专门针对癌症特异性p110α突变体的抑制剂是当前药物开发的重要目标和挑战。
Class I phosphoinositide 3-kinase (PI3K) is a dimeric enzyme, consisting of a catalytic and a regulatory subunit. The catalytic subunit occurs in four isoforms designated as p110α, p110β, p110γ and p110δ. These combine with several regulatory subunits; for p110α, β and δ the standard regulatory subunit is p85, for p110γ it is p101. PI3Ks play important roles in human cancer. PIK3CA, the gene encoding p110α, is mutated frequently in common cancers, including carcinoma of the breast, prostate, colon and endometrium. Eighty percent of these mutations are represented by one of three amino acid substitutions in the helical or kinase domains of the enzyme. The mutant p110α shows a gain of function in enzymatic and signaling activity and is oncogenic in cell culture and in animal model systems. Structural and genetic data suggest that the mutations affect regulatory inter- and intramolecular interactions and support the conclusion that there are at least two molecular mechanisms for the gain-of-function in p110α. One of these mechanisms operates largely independently of binding to p85, the other abolishes the requirement for an interaction with Ras. The non-alpha isoforms of p110 do not show cancer-specific mutations. However, they are often differentially expressed in cancer and, in contrast to p110α, wild-type non-alpha isoforms of p110 are oncogenic when overexpressed in cell culture. The isoforms of p110 have become promising drug targets. Isoform-selective inhibitors have been identified. Inhibitors that target exclusively the cancer-specific mutants of p110α constitute an important goal and challenge for current drug development.
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