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. 2014 Jan 13;6(1):79–111. doi: 10.3390/cancers6010079

Figure 7.

Figure 7

Cdk inhibitors p21 and p27 are deregulated in HCC. Low expression level of HCV expression core protein activates p53, which induces expression of p21 while high expression level of its mature form activates miR-345 targeting p21 mRNA. HBV X protein (HBx) results in bivalent actions on the transcription of the p21 gene by activating Ets1 or repressing Sp1 transcription factors. p27 mRNA is targeted by miR-221, which is often upregulated in HCC. p21 and p27 are phosphorylated by Cdk2 or Cdk4 respectively on S130 and T187 and ubiquitinated by Skp2 resulting in p21 and p27 degradation. Skp2 is targeted for degradation by the APC/C complex, itself regulated by Emi1, which is frequently overexpressed in HCC like Skp2. p27 is not only down regulated in HCC, its overexpression is a result of phosphorylation on T157 by Akt/PKB, leading to export of p27 to the cytoplasm where it is sequestered by Cdk4/cyclin D complexes.