[pRB, p53, p16INK4a, senescence and malignant transformation]

Recent works aimed at clarifying the respective roles of p16INKa and p14ARF (both located on the same INK4a locus on chromosome 9p21 in man) in malignant transformation come to the conclusion that p16INK4a is the true tumor suppressor gene in man. In mouse, it is the p19ARF knockout that suppresses the barrier protecting cells from malignant transformation. This situation is in agreement with p19ARF- and p16-mediated senescence induced by oncogenic mutated ras (Ras*) in mouse and man respectively. Other results have shown that senescence in human diploid fibroblasts is associated with heterochromatin occurrence that maintains in repressed state E2F1-induced gens required for G1 to S phases transition. Since RB protein is responsible for this chromatin modification, cells with any impaired RB pathway cannot enter into senescence.