Prevalent overexpression of prolyl isomerase Pin1 in human cancers
Prevalent overexpression of prolyl isomerase Pin1 in human cancers
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DOI：
10.1016/s0002-9440(10)63731-5
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发表时间：
2004-05-01
影响因子：
6
通讯作者：
Wang, DG
中科院分区：
文献类型：
--
作者：
Bao, L;Kimzey, A;Wang, DG
脯氨酸之前的丝氨酸或苏氨酸残基上的蛋白质磷酸化（pSer/Thr-Pro）是细胞增殖和转化的主要调节机制。有趣的是，蛋白质中的pSer/Thr-Pro基序以两种不同的顺式和反式构象存在，其转化率通常在磷酸化时降低，但由脯氨酰异构酶Pin 1特异性催化。Pin 1可以催化诱导蛋白质磷酸化后的构象变化，从而对某些磷酸化蛋白质的催化活性、去磷酸化、蛋白质-蛋白质相互作用、亚细胞定位和/或周转具有深远的影响。最近，已经表明Pin 1在人乳腺癌细胞系和癌组织中过表达，并且通过激活多种致癌途径在乳腺上皮细胞的转化中起关键作用。此外，Pin 1表达是前列腺癌的一个极好的独立预后标志物。然而，很少有人知道Pin 1在其他人类正常和癌组织中的表达。在本研究中，我们定量了2041例人类肿瘤样本和609例正常组织样本以及正常和转化的人类细胞系中的Pin 1表达。我们发现Pin 1在大多数正常组织中通常以非常低的水平表达，并且其表达通常与细胞增殖相关，仅在少数细胞类型中发现高Pin 1水平。然而，Pin 1在许多不同的人类癌症中显著过表达。与相应的正常对照相比，大多数肿瘤（60种肿瘤类型中的38种）在超过10%的病例中Pin 1过表达，其中包括前列腺、肺、卵巢、宫颈、脑肿瘤和黑色素瘤。与这些发现一致，Pin I在人癌细胞细颗粒中的表达也高于所检查的正常细胞系。这些结果表明，Pin 1过表达是人类癌症中普遍和特异的事件。鉴于先前的发现，Pin 1表达是前列腺癌中一个很好的预后标志物，并且Pin 1的抑制可以抑制转化的表型并抑制肿瘤细胞生长，这些发现可能对人类癌症的发病机制，诊断和治疗具有重要意义。
Phosphorylation of proteins on serine or threonine residues preceding proline (pSer/Thr-Pro) is a major regulatory mechanism in cell proliferation and transformation. Interestingly, the pSer/Thr-Pro motifs in proteins exist in two distinct cis and trans conformations, whose conversion rate is normally reduced on phosphorylation, but is catalyzed specifically by the prolyl isomerase Pin1. Pin1 can catalytically induce conformational changes in proteins after phosphorylation, thereby having profound effects on catalytic activity, dephosphorylation, protein-protein interactions, subcellular location, and/or turnover of certain phosphorylated proteins. Recently, it has been shown that Pin1 is overexpressed in human breast cancer cell lines and cancer tissues and plays a critical role in the transformation of mammary epithelial cells by activating multiple oncogenic pathways. Furthermore, Pin1 expression is an excellent independent prognostic marker in prostate cancer. However, little is known about Pin1 expression in other human normal and cancerous tissues. In the present study, we quantified Pin1 expression in 2041 human tumor samples and 609 normal tissue samples as well as normal and transformed human cell lines. We found that Pin1 was usually expressed at very low levels in most normal tissues and its expression was normally associated with cell proliferation, with high Pin1 levels being found only in a few cell types. However, Pin1 was strikingly overexpressed in many different human cancers. Most tumors (38 of 60 tumor types) have Pin1 overexpression in more than 10% of the cases, as compared with the corresponding normal controls, which included prostate, lung, ovary, cervical, brain tumors, and melanoma. Consistent with these findings, Pin I expression in human cancer cell fines was also higher than that in the normal cell lines examined. These results indicate that Pin1 overexpression is a prevalent and specific event in human cancers. Given previous findings that Pin1 expression is an excellent prognostic marker in prostate cancer and that inhibition of Pin1 can suppress transformed phenotypes and inhibit tumor cell growth, these findings may have important implications for the pathogenesis, diagnosis, and treatment of human cancers.