Denicourt Catherine, Saenz Cheryl C, Datnow Brian, Cui Xian-Shu, Dowdy Steven F
Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California at San Diego School of Medicine, La Jolla, California 92037-0686, USA.
Cancer Res. 2007 Oct 1;67(19):9238-43. doi: 10.1158/0008-5472.CAN-07-1375.
The p27 tumor suppressor negatively regulates G1 cell cycle progression. However, human malignancies rarely select for deletion/inactivation of p27, a hallmark of tumor suppressor genes. Instead, p27 is degraded or relocalized to the cytoplasm in aggressive malignancies, supporting the notion that p27 sequestration from its nuclear cyclin:cyclin-dependent kinase (cdk) targets is critical. However, emerging cell biology data suggest a novel cdk-independent cytoplasmic function of p27 in cell migration. Here, we find cytoplasmic p27 in 70% of invasive and metastatic melanomas. In contrast, no cytoplasmic p27 was detected in noninvasive, basement membrane-confined melanoma in situ, suggesting a late oncogenic role for cytoplasmic p27 in metastasis. Targeted cytoplasmic expression of wild-type or non-cdk-binding p27 at subphysiologic levels induced melanoma motility and resulted in numerous metastases to lymph node, lung, and peritoneum. These observations point to a prominent role of cytoplasmic p27 in metastatic disease that is independent of cyclin:cdk regulation or mere nuclear loss.
p27肿瘤抑制因子对G1期细胞周期进程起负调控作用。然而，人类恶性肿瘤很少通过缺失/p27失活来选择，而这是肿瘤抑制基因的一个标志。相反，在侵袭性恶性肿瘤中，p27会降解或重新定位于细胞质，这支持了一种观点，即p27与其核细胞周期蛋白：细胞周期蛋白依赖性激酶（cdk）靶点的隔离至关重要。然而，新出现的细胞生物学数据表明p27在细胞迁移中具有一种新的不依赖cdk的细胞质功能。在此，我们在70%的侵袭性和转移性黑色素瘤中发现了细胞质p27。相比之下，在非侵袭性、局限于基底膜的原位黑色素瘤中未检测到细胞质p27，这表明细胞质p27在转移中具有晚期致癌作用。在亚生理水平靶向细胞质表达野生型或不与cdk结合的p27可诱导黑色素瘤的运动性，并导致大量转移至淋巴结、肺和腹膜。这些观察结果表明细胞质p27在转移性疾病中具有重要作用，该作用独立于细胞周期蛋白：cdk调控或单纯的核丢失。
