The tumor-suppressive functions of the human INK4A locus

The INK4A locus is often inactivated in human cancer. INK4A encodes for p14(ARF) and p16(INK4A) that inhibit growth through p53 and pRb, respectively. We used RNA interference vectors in transformation assays of human primary cells to analyze tumor-suppressive functions. We first show that a concerted inactivation of pRb and p53 is required for transformation. We then demonstrate that loss of p14(ARF) enhances growth in a p53-dependent manner but has little tumorigenic effect. In contrast, suppression of p16(INK4A) expression does not affect cellular proliferation but synergizes with p53 loss to accelerate growth and cause transformation. Our results delineate the functions of the human INK4A genes in normal and tumorigenic growth.