Prolyl isomerase Pin1 as a molecular target for cancer diagnostics and therapeutics
Prolyl isomerase Pin1 as a molecular target for cancer diagnostics and therapeutics
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DOI：
10.1016/s1535-6108(03)00218-6
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发表时间：
2003-09-01
期刊：
影响因子：
50.3
通讯作者：
Lu, KP
中科院分区：
文献类型：
--
作者：
Lu, KP
癌症是一系列疾病的集合，其共同特征是不受控制的细胞增殖。紧接在脯氨酸之前的丝氨酸或苏氨酸残基上的蛋白质的磷酸化（pSer/Thr-Pro），所谓的Pro定向磷酸化，是控制正常细胞增殖和恶性转化的中心信号传导机制（Blume-Jensen和Hunter，2001; Lu等人，2002年b）。丝氨酸/苏氨酸-脯氨酸基序是许多脯氨酸蛋白激酶的磷酸化位点，在信号转导和细胞周期进程中起重要作用。此外，许多癌基因和抑癌基因本身也受Pro磷酸化的直接调控和/或可触发与Pro磷酸化有关的信号通路，对Pro磷酸化的调控机制及其生理功能和病理意义的研究已取得重要进展。然而，很少有人知道大多数丝氨酸/苏氨酸磷酸化事件如何调节蛋白质的功能，虽然磷酸化诱导的构象变化已被提出发挥重要的调节作用。最近对肽基-脯氨酰顺式/反式异构酶（PPI酶）Pin 1的鉴定和表征，其特异性地调节某些蛋白质中特定的前定向磷酸化位点的构象，已经导致发现了新的磷酸化后调节机制（Lu等人，1996，2002 b; Ranganathan等人，1997; Yaffe等人，1997年）。在这种机制中，Pin 1结合并异构化特定的pSer/Thr-Pro基序，并在磷酸化后催化诱导构象变化。这样的构象变化可以对许多Pin 1底物的功能具有深远的影响，从而在许多细胞事件中发挥重要作用，例如细胞周期进展、转录调节、RNA加工以及细胞增殖和分化（Lu et al.，2002年b）。值得注意的是，Pin 1不仅在大量人类癌症中过表达，而且在一些癌症中是极好的预后标志物（Ayala et al.，2003; L. Bao等人，提交; Ryo等人，2001; Wulf等人，2001年）。此外，Pin 1过表达可作为在肿瘤发生期间放大多种致癌信号传导途径的关键催化剂（Liou et al.，2002; Ryo等人，2001，2002，2003; Wulf等人，2001年）。值得注意的是，通过多种方法抑制癌细胞中的Pin 1触发细胞凋亡或抑制转化的表型（Lu等人，1996; Rippmann等人，2000; Ryo等人，2002年）。此外，正在鉴定可以选择性抑制Pin 1的化合物（Hennig等人，1998; Uchida等人，2003年）。这些结果表明，Pin 1介导的磷酸化后调节可能提供了一个独特的机会，破坏致癌途径，并代表了一个有吸引力的新的抗癌疗法的目标。本综述的主要重点是讨论
Cancer is a collection of diseases whose common feature is uncontrolled cell proliferation. The phosphorylation of proteins on serine or threonine residues that immediately precede a proline (pSer/Thr-Pro), so-called Pro-directed phosphorylation, is a central signaling mechanism controlling normal cell proliferation and malignant transformation (Blume-Jensen and Hunter, 2001; Lu et al., 2002b). Ser/Thr-Pro motifs are the exclusive phosphorylation sites for a large number of Pro-directed protein kinases that play essential roles in signal transduction and cell cycle progression. Furthermore, many oncogenes and tumor suppressors themselves are directly regulated by Pro-directed phosphorylation and/or can trigger signaling pathways involving Pro-directed phosphorylation.Significant progress has been made in elucidating the mechanisms controlling Pro-directed phosphorylation and its physiological function and pathological importance. However, little is known about how most Ser/Thr phosphorylation events regulate protein function, although phosphorylation-induced conformational changes have been proposed to play a significant regulatory role. The recent identification and characterization of a peptidyl-prolyl cis/trans isomerase (PPIase), Pin1, which specifically regulates the conformation of specific Prodirected phosphorylation sites in certain proteins, has led to the discovery of a new postphosphorylation regulatory mechanism (Lu et al., 1996, 2002b; Ranganathan et al., 1997; Yaffe et al., 1997). In this mechanism, Pin1 binds to and isomerizes specific pSer/Thr-Pro motifs and catalytically induces conformational changes following phosphorylation. Such conformational changes can have profound effects on the function of many Pin1 substrates, thereby playing an important role in many cellular events, such as cell cycle progression, transcriptional regulation, RNA processing, and cell proliferation and differentiation (Lu et al., 2002b). Notably, Pin1 is not only overexpressed in a large number of human cancers, but also is an excellent prognostic marker in some cancers (Ayala et al., 2003; L. Bao et al., submitted; Ryo et al., 2001; Wulf et al., 2001). Furthermore, Pin1 overexpression can function as a critical catalyst that amplifies multiple oncogenic signaling pathways during oncogenesis (Liou et al., 2002; Ryo et al., 2001, 2002, 2003; Wulf et al., 2001). Significantly, inhibition of Pin1 in cancer cells via multiple approaches triggers apoptosis or suppresses transformed phenotype (Lu et al., 1996; Rippmann et al., 2000; Ryo et al., 2002). In addition, compounds that may selectively inhibit Pin1 are being identified (Hennig et al., 1998; Uchida et al., 2003). These results suggest that Pin1-mediated postphosphorylation regulation may provide a unique opportunity for disrupting oncogenic pathways and represent an appealing target for novel anticancer therapies. The primary focus of this review is to discuss