p27. MicroRNA regulation Because p27 levels can be moderated at the translational level, it has been proposed that p27 may be regulated by miRNAs. Recent research has suggested that both miR-221 and miR-222 control p27 levels although the pathways are not well understood. Role in cancer Proliferation p27 is considered a tumor suppressor because of its function as a regulator of the cell cycle. In cancers it is often inactivated via impaired synthesis, accelerated degradation, or mislocalization. Inactivation of p27 is generally accomplished post-transcription by the oncogenic activation of various pathways including receptor tyrosine kinases (RTK), phosphatilidylinositol 3-kinase (PI3K), SRC, or Ras-mitogen activated protein kinase(MAPK). These act to accelerate the proteolysis of the p27 protein and allow the cancer cell to undergo rapid division and uncontrolled proliferation. When p27 is phosphorylated by Src at tyrosine 74 or 88 it ceases to inhibit cyclinE-cdk2. Src was also shown to reduce the half life of p27 meaning it is degraded faster. Many epithelial cancers are known to overexpress EGFR which plays a role in the proteolysis of p27 and in Ras-driven proteolysis. Non-epithelial cancers use different pathways to inactivate p27. Many cancer cells also upregulate Skp2 which is known to play an active role in the proteolysis of p27 As a result, Skp2 is inversely related to p27 levels and directly correlates with tumor grade in many malignancies. Metastasis In cancer cells, p27 can also be mislocalized to the cytoplasm in order to facilitate metastasis. The mechanisms by which it acts on motility differ between cancers. In hepatocellular carcinoma cells p27 co-localizes with actin fibers to act on GTPase Rac and induce cell migration. In breast cancer cytoplasmic p27 reduced RHOA activity which increased a cell's propensity for motility. This role for p27 may indicate why cancer cells rarely fully inactivate or delete p27. By retaining p27 in some capacity it can be exported to the cytoplasm during tumorigenesis and manipulated to aid in metastasis. 70% of metastatic melanomas were shown to exhibit cytoplasmic p27, while in benign melanomas p27 remained localized to the nucleus. P27 is misplaced to the cytoplasm by the MAP2K, Ras, and Akt pathways although the mechanisms are not entirely understood. Additionally, phosphorylation of p27 at T198 by RSK1 has been shown to mislocalize p27 to the cytoplasm as well as inhibit the RhoA pathway. Because inhibition of RhoA results in a decrease in both stress fibers and