Suizu Futoshi, Ryo Akihide, Wulf Gerburg, Lim Jormay, Lu Kun Ping
Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Mol Cell Biol. 2006 Feb;26(4):1463-79. doi: 10.1128/MCB.26.4.1463-1479.2006.
Phosphorylation on Ser/Thr-Pro motifs is a major mechanism regulating many events involved in cell proliferation and transformation, including centrosome duplication, whose defects have been implicated in oncogenesis. Certain phosphorylated Ser/Thr-Pro motifs can exist in two distinct conformations whose conversion in certain proteins is catalyzed specifically by the prolyl isomerase Pin1. Pin1 is prevalently overexpressed in human cancers and is important for the activation of multiple oncogenic pathways, and its deletion suppresses the ability of certain oncogenes to induce cancer in mice. However, little is known about the role of Pin1 in centrosome duplication and the significance of Pin1 overexpression in cancer development in vivo. Here we show that Pin1 overexpression correlates with centrosome amplification in human breast cancer tissues. Furthermore, Pin1 localizes to and copurifies with centrosomes in interphase but not mitotic cells. Moreover, Pin1 ablation in mouse embryonic fibroblasts drastically delays centrosome duplication without affecting DNA synthesis and Pin1 inhibition also suppresses centrosome amplification in S-arrested CHO cells. In contrast, overexpression of Pin1 drives centrosome duplication and accumulation, resulting in chromosome missegregation, aneuploidy, and transformation in nontransformed NIH 3T3 cells. More importantly, transgenic overexpression of Pin1 in mouse mammary glands also potently induces centrosome amplification, eventually leading to mammary hyperplasia and malignant mammary tumors with overamplified centrosomes. These results demonstrate for the first time that the phosphorylation-specific isomerase Pin1 regulates centrosome duplication and its deregulation can induce centrosome amplification, chromosome instability, and oncogenesis.
丝氨酸/苏氨酸-脯氨酸基序上的磷酸化是调节细胞增殖和转化中许多事件的主要机制，包括中心体复制，其缺陷与肿瘤发生有关。某些磷酸化的丝氨酸/苏氨酸-脯氨酸基序可以以两种不同的构象存在，某些蛋白质中它们的构象转换由脯氨酰异构酶Pin1特异性催化。Pin1在人类癌症中普遍过表达，对多种致癌途径的激活很重要，其缺失可抑制某些癌基因在小鼠中诱导癌症的能力。然而，关于Pin1在中心体复制中的作用以及Pin1过表达在体内癌症发展中的意义知之甚少。在这里，我们表明Pin1过表达与人类乳腺癌组织中的中心体扩增相关。此外，Pin1在间期而非有丝分裂细胞中定位于中心体并与中心体共纯化。此外，在小鼠胚胎成纤维细胞中敲除Pin1会大幅延迟中心体复制，而不影响DNA合成，并且抑制Pin1也会抑制S期停滞的CHO细胞中的中心体扩增。相反，Pin1的过表达驱动中心体复制和积累，导致染色体错分离、非整倍体和未转化的NIH 3T3细胞发生转化。更重要的是，在小鼠乳腺中转基因过表达Pin1也能有效诱导中心体扩增，最终导致乳腺增生和带有过度扩增中心体的恶性乳腺肿瘤。这些结果首次证明，磷酸化特异性异构酶Pin1调节中心体复制，其失调可诱导中心体扩增、染色体不稳定和肿瘤发生。
