Figure 1. p27 as a tumor-suppressor protein. a, In normal epithelial cells, anti-mitogenic signals, such as TGF- or IL-6, act to inhibit growth. They do so by mobilizing p27 to inhibit cyclin E-cdk2. This prevents the activation of S phase-specific transcription factors, such as E2F, and cells become arrested in the G1 phase of the cell cycle. Thus, p27 helps to maintain homeostasis in epithelial cells. b, In many carcinoma cells, the Akt pathway is overstimulated. Overstimulation can occur through oncogenic activation of tyrosine kinase receptors, such as HER2, inactivation of Pten or activation of Akt itself. Activation allows Akt to phosphorylate p27 on a threonine residue in its NLS, impeding nuclear entry of p27. Thus relegated to the cytoplasm, p27 is unable to control cdk2, which can remain active in the nucleus even in the presence of anti-mitogenic signals. Unrestricted cdk2 would activate E2F and allow unchecked cell proliferation. Therefore, barring p27 from the nucleus has hypothetically the same effect as loss of the protein.