p16(INK4a) and p21(WAF1), two major cyclin-dependent kinase inhibitors, are the products of two tumor suppressor genes that play important roles in various cellular metabolic pathways. p21(WAF1) is up-regulated in response to different DNA damaging agents. While the activation of p21(WAF1) is p53-dependent following gamma-rays, the effect of ultraviolet (UV) light on p21(WAF1) protein level is still unclear. In the present report, we show that the level of the p21(WAF1) protein augments in response to low UVC fluences in different mammalian cells. This up-regulation is mediated through the stabilization of p21(WAF1) mRNA in a p16(INK4a)-dependent manner in both human and mouse cells. Furthermore, using p16-siRNA treated human skin fibroblast; we have shown that p16 controls the UV-dependent cytoplasmic accumulation of the mRNA binding HuR protein. In addition, HuR immunoprecipitations showed that UV-dependent binding of HuR to p21 mRNA is p16-related. This suggests that p16 induces p21 by enabling the relocalization of HuR from the nucleus to the cytoplasm. Accordingly, we have also shown that p16 is necessary for efficient UV-dependent p53 up-regulation, which also requires HuR. These results indicate that, in addition to its role in cell proliferation, p16(INK4a) is also an important regulator of the cellular response to UV damage.