Relocalized p27Kip1 tumor suppressor functions as a cytoplasmic metastatic oncogene in melanoma

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 p...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2007-10, Vol.67 (19), p.9238-9243
Main Authors: Denicourt, Catherine, Saenz, Cheryl C, Datnow, Brian, Cui, Xian-Shu, Dowdy, Steven F
Format: Article
Language:English
Subjects:
Animals
Cell Movement - physiology
Cyclin-Dependent Kinase Inhibitor p27 - deficiency
Cyclin-Dependent Kinase Inhibitor p27 - genetics
Cyclin-Dependent Kinase Inhibitor p27 - metabolism
Cytoplasm - genetics
Genes, Tumor Suppressor
Humans
Immunohistochemistry
Melanoma - genetics
Melanoma - metabolism
Melanoma - pathology
Melanoma, Experimental - genetics
Melanoma, Experimental - metabolism
Melanoma, Experimental - pathology
Mice
Mice, Inbred C57BL
Neoplasm Invasiveness
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-07-1375