The yin and the yang of p27Kip1 as a target for cancer therapy

Schematically, human tumours arise because tumour cells escape from extracellular signals that physiologically monitor cellular proliferation, as well as cell death, and acquire the property to grow continuously. During tumourigenesis, many proteins that normally control the proper timing of cell growth, e.g. the cyclins, or prevent the occurrence of unappropriate apoptosis are abnormally expressed or activated, and act as typical oncogenes leading to hyperproliferation and/or protecting tumour cells from death. In contrast, proteins that normally prevent, for example, damaged cells to progress into the next phase of the cell cycle or act as apoptosis inducers, if the damage can not be repaired, are frequently inactivated in tumour cells and act as tumour suppressor genes. Therefore, loss of tumour suppressor genes associated with abnormal hyperactivity of oncogenes classically contribute to human carcinogenesis. However, affecting a clear-cut function of tumour suppressor or oncogene remains a subject of debate for certain proteins. The p27Kip1 is a member of the cyclin-dependent kinase inhibitory proteins, which also include: p21WAF1, the target gene of p53; p16INK4a, a member of the retinoblastoma (Rb) pathway; and p57Kip2. In combination with p16INK4a, it plays a major role in counteracting the activity of cyclins D1 and E on Rb phosphorylation and subsequent G1‐S transition. Therefore, it coordinates …