Damage Signals from p53

Abstract

In response to DNA damage, the tumor suppressor protein p53 moves to the nucleus and activates transcription of target genes. Two papers appearing this week explore aspects of how this signaling is accomplished. Giannakakou et al . find that p53 associates with tubulin, preferably the polymerized form of tubulin in microtubules. Furthermore, they show that transport of p53 to the nucleus in response to DNA damage in human lung carcinoma cells is inhibited by agents that either stabilize or destabilize microtubules or by agents that impair the activity of the microtubule-motor protein dynein. Once it gets to the nucleus, what does p53 do? Guo et al . conclude that it interacts with the product of the PML gene. In acute promyelocytic leukemia, the PML gene undergoes a chromosomal translocation, resulting in formation of a chimeric oncoprotein. The wild-type PML protein localizes in nuclear structures called PML nuclear bodies and functions in the regulation of transcription. Guo et al . describe several experiments that indicate that PML functions to promote signals that induce apoptosis in response to DNA damage. Mouse thymocytes lacking PML were less susceptible than control cells to DNA damage-induced cell death. PML interacted in vivo and in vitro with p53 and, in reporter assays in transfected cells, expression of PML increased transcriptional activation by p53. And finally, transcription of p53 target genes in cells exposed to gamma irradiation was reduced in cells lacking PML. Thus, the PML protein appears to promote apoptosis, at least in part, by acting as a transcriptional coactivator with p53. Giannakakou, P., Sackett, D.L., Ward, Y., Webster, K.R., Blagosklonny, M.V., and Fojo, T. (2000) p53 is associated with cellular microtubules and is transported to the nucleus by dynein. Nature Cell Biol . 2 : 709-717. [Online Journal] Guo, A., Salomoni, P., Luo, J., Shih, A., Zhong, S., Gu, W., and Pandolfi, P.P. (2000) The function of PML in p53-dependent apoptosis. Nature Cell Biol . 2 : 730-736. [Online Journal]