Peking University, Beijing, Apr. 15, 2010: Researchers from Institute for Cancer Genetics, Columbia University, Peking University Health Science Center and Baylor College of Medicine have discovered a new mechanism in p53 activation mediated by ARF, as well as a new kind enzyme. This discovery, illustrating the role the new enzyme is playing in p53 activation, has been published on the Nature magazine.
The leading researcher in this project is Prof. Gu Wei in Columbia University, who graduated from Peking University and went to the US for advanced studies in1992. He stayed at Columbia University to teach after graduation. His current research focus is on the function p53 plays in suppressing tumor and the aging of p53. He has made outstanding achievements in the field of p53 and published dozens of treatises on high-level magazines, for example, Nature, Cell, Science, Mol. Cell, and Mol Cell Biol, etc.
Tumor suppressors are the kind of gene preventing cells from excessive growth and proliferation to suppress tumorigenesis. For normal human cells, coordination between growth-promoting genes and growth-controlling ones is a significant mechanism in determining the growth of cells. Until now, there have been 10 defined tumor suppressors, among which p53 is a better known one. It is titled “Defender of Genes” because it plays an important part in sustaining normal growth of cells and in suppressing vicious proliferation of them.
Under oncogenic stress, p53 activation needs a tumor suppressor gene called ARF. Recent studies showed that p53 activation mediated by ARF, instead of being induced by DNA damage, acts as a major protection against tumorigenesis, suggesting that ARF-p53 axis has more fundamental functions in tumor suppression than originally thought.
Because ARF is a very stable protein in most human cell lines, scientists hold that ARF induction is mediated mainly at the transcriptional level and that activation of the ARF-p53 pathway is a much slower and largely irreversible process by comparison with p53 activation after DNA damage.
In this treatise, researchers find that ARF is very unstable in normal human cells but that its degradation is inhibited in cancerous cells. Through biochemical purification, they identified a specific ubiquitin ligase for ARF and named it ULF. ULF interacts with ARF both in vitro and in vivo and promotes degradation of ARF. The experiment of ULF knockdown confirms that it stabilizes ARF in normal human cells.
Moreover, it is discovered that NPM and c-Myc, both of which are commonly over-expressed proteins in cancer cells, are able to abrogate ULF-mediated ARF ubiquitylation, and therefore promote ARF stabilization in cancer cells. These findings reveal the dynamic feature of the ARF-p53 pathway and illustrate that transcription-independent mechanisms are of critical importance to ARF regulation.
Prof. Gu Wei's research team has made many important discoveries in the area of p53. He published another treatise in Cell magazine, depicting p53's controlling mode.
It is traditionally thought that p53 activation undergoes three steps: p53 stabilization, DNA binding and transcriptional activation. Nevertheless, this old theory is not in accordance with new findings which point out every step in p53 activation pathway is much more complicated than imagined.
The results in experiment of genetics studies in vivo and in vitro modeled by mice show that traditional theory cannot explain many phenomena. Therefore, views on p53 must be updated in order to construct an overall p53 regulating theory. Prof. Gu Wei proposes that anti-repression is a critical step in p53 activation.
Translated by: Zhang Chunlan
Edited by: Seren
Source: PKU News (Chinese)
