Relocalized p27Kip1 Tumor Suppressor Functions as a Cytoplasmic Metastatic Oncogene in Melanoma

Abstract

The p27 tumor suppressor negatively regulates G 1 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 membraneconfined 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]

Siah1/SIP regulates p27kip1stability and cell migration under metabolic stress

“…Moreover, accumulation of cytoplasmic p27 protein has been recognized to be associated with tumor malignancies, suggesting a role in tumor invasion. 16,17,43,44 Therefore, we explored the effect of SIP on cell motility. Initially, cell migration was monitored using transwell chambers that were seeded with MEFs derived from wild-type or SIP -/-embryos using low or high serum that was supplemented (or not) with glucose.…”

“…[13][14][15] Moreover, accumulation of cytoplasmic p27 protein has also been reported in other human malignancies. 16,17 The gene encoding p27 is rarely mutated in tumor cells that express low levels of the protein, suggesting an important role for post-transcriptional mechanisms in p27 turnover. Indeed, nuclear p27 is degraded by the SCF Skp2 complex during late G 1 phase.…”

TGFβ prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest

“…44,74,75 Accordingly, cytoplasmic sequestration of p27 has been shown to be a poor prognostic indicator in various human cancers. 44,76,77 The association of elevated cyclin D with mammary tumor cell migration was shown to be dependent on the presence of cytoplasmic p27 phosphorylated at S10, 78 and evidently, splice variants of cyclin D1 are modulators of p27 migration. 79 Alternatively, in the cytoplasm unphosphorylated p27 can be targeted for proteasomal degradation by the E3 ligase, KPC1.…”

“…The lack of nuclear p27 has been found in numerous types of human cancer 41,42 and cytoplasmic sequestration of this protein is associated with decreased survival. 43,44 Conversely, Skp2 is elevated in human cancers and correlates with high malignant grade. [45][46][47] Moreover, the functional inverse relationship between p27 and Skp2 is recapitulated in many of these cancers.…”

Formation of E-Cadherin/β-Catenin–based Adherens Junctions in Hepatocytes Requires Serine-10 in p27(Kip1)

“…Activation of MAPK by OSM also influences the expression of p27(Kip1); see Klausen et al (2000). p27(Kip1) controls cell cycle progression (Polyak et al, 1994) and, interestingly, displays additional non-cell cycle-related functions including differentiation (Deschênes et al, 2001), apoptosis (Drexler, 2003), and migration (McAllister et al, 2003;Besson et al, 2004;Denicourt et al, 2007). The main phosphorylation site in p27(Kip1), Ser10, has been proposed to be an important determinant for non-cell cycle-related cytoplasmic functions of p27(Kip1) (see McAllister et al, 2003;Besson et al, 2006).…”