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Relocalized p27^Kip1 Tumor Suppressor Functions as a Cytoplasmic Metastatic Oncogene in Melanoma

¹ Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, ² Department of Reproductive Medicine, and ³ Department of Pathology, University of California at San Diego School of Medicine, La Jolla, California

Requests for reprints: Steven F. Dowdy, Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California at San Diego School of Medicine, 9600 Gilman Drive, La Jolla, CA 92037-0686. Phone: 858-534-7772; E-mail: sdowdy{at}ucsd.edu.

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. [Cancer Res 2007;67(19):9238–43]

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