癌化の2つの基本経路: RB経路とp53経路

抄録

Many acumulating data have suggested that most of signals of oncoproteins and tummor suppressor proteins are transmitted to two basic pathways: the RB pathway and the p53 pathway. In fact, mutations are detected in both of these pathways in almost 100% of cancers.
Upon DNA damage, p53 protein accumulates rapidly through a posttranscriptional mechanism (s) and is also activated as a transcription factor, which then leads to growth arrest or apoptosis. We have generated antibodies which recognize most of the potential phosphorylation (13 sites) and acetylation sites (3 sites) of p53, and using these antibodies, we have shown that phosphorylation of human p53 at serine 15 and 20 occurs after DNA damage and that this leads to reduced interaction of p53 with its negative regulator, MDM2. Subsequently, we have also shown that ATM protein has intrinsic protein kinase activity and that it phosphorylates Ser15 of p53.
It is an important question how two different pathways, apoptosis and Gl-arrest, are selected by p53. We have now found that phosphorylation of Ser46 regulates apoptosis-inducing ability of p53. Dr. Yusuke Nakamura's lab. has isolated such a candidate apoptosis-inducing gene which is regulated by phosphorylation of Ser46 of p53. It is p53AIPl (p53-regulated Apoptosis Inducing Protein 1) . It appears that swich between promoters of Gl-arrest and apoptosis genes occurs by Ser46 phosphorylation. This mechanism can be applied for development of a new cancer therapy method without side effects caused by DNA damage in normal cells. [Skin Cancer (Japan) 2001; 16: 7-12]