Genes Dev: Gu Wei Lab's ultimate weapon in analyzing p53's anti-cancer function , Iron Death and mTOR

It is well known that p53 is a cancer-suppressing gene with a wide range of powerful functions.
more than half of cancer patients have p53 mutations.
p53 gene knock-out (KO) mice form tumors early in development.
p53 gene has been a hot topic in molecular biology and oncology since it was discovered in 1979.
a 2017 statistic in the journal Nature, p53 ranked first on the list of the most popular research genes of the past few decades.
more than 40 years of research has revealed the various mechanisms of p53 in suppressing tumors.
p53 mainly as a transcription factor, activating or inhibiting the transcription of a variety of downstream target genes to form functions.
the role of these target genes mainly include inducing cell cycle stagnation, DNA repair, cell metabolic changes, cell aging, apoptosis, and newly discovered induced cell iron death (ferroptosis).
, how does p53 regulate these functions, and which of these functions/which ones really suppress tumors? There has been some controversy in academia on these two issues.
until 2012, academics thought that p53 induced cell cycle stagnation, aging or apoptosis (cell cycle arrest, senescence and apoptosis) was enough to explain its anti-cancer function.
in 2012-2013, three studies (two Cells and one Cell Reports) overturned this view.
most famous of these articles came from Professor Gu Wei's lab at Columbia University School of Medicine (Cell, 2012).
Gu Wei is one of the world's authoritative scientists in the field of p53.
in more than two decades of research, Professor Gu Wei's lab has resulted in a number of important achievements in p53 function and regulation (the main conclusions are published in more than a dozen CNS journals and several CNS sub-issues).
one of the most important findings of this study is that it reveals the importance of acetylation modifications for p53 functionality.
as early as 1997, Professor Gu Wei pioneered the discovery that p53's C-side domain could be modified with CBP acetylation to promote protein stability and function (Cell, 1997).
this is one of the first studies in academia to report that acetylation modification can also occur in non-histamines after the detection of protein acetylation modification.
study also kicked off a research boom in non-histoprotein acetylation modifications.
in 2006, Gu Wei's lab discovered that p53 K120 could be modified with acetylation (Mol cell, 2006).
acetylation-missing mutants with p53 K120R lose the ability to activate the PUMA gene and thus cannot induce apoptosis.
this mutant p53 is also known as p53 1KR.
two years later, Gu Wei's lab continued to identify the occurrence of acetylation in p53,164 bits (corresponding to 161 and 162 bits in mice) (Cell, 2008).
the K-R mutation at this point will cause p53 to lose the ability to activate p21 and induce cell cycle stagnation and cell aging.
In 2012, using p53 3KR (120, 161 and 162) mutant mice, Professor Gu Wei and others found that p53 could still have anti-cancer function after losing the induced cell cycle that induces three classic anti-cancer functions, aging or apoptosis (Cell, 2012).
, p53 3KR can activate some metabolically related target genes while losing the ability to activate multiple traditional p53 target genes (PUMA, NOXA, p21, etc.).
suggests that regulating metabolism may be the key to p53 suppressing tumors.
2015, Professor Gu Wei's team first revealed that p53 can promote cell iron death by inhibiting the cysteine-glutamate transporter SLC7A11 (Nature, 2015).
this function is regulated by p53 101-bit (98-bit corresponding to mice) acetylation modification (Cell Reports, 2017).
so on the basis of 3KR, and then eliminate the function of p53 mediated iron death, can make p53 no longer be able to suppress tumors? In an article published online December 10 in the journal Genes and Development, Gu Wei's team's latest research answers this question.
based on previous research, Gu Wei's team first constructed p53 4KR (3KR plus 98 KR mutations) mice.
3KR mice were similar to normal mice and rarely produced tumors.
, the proportion of tumors produced in 4KR mice increased significantly in the later stages of growth after further loss of the function that induced iron death.
results show that induced iron death is one of the important mechanisms for p53 to suppress tumors.
, although 4KR mice had a much higher risk of cancer than normal mice, they did not develop tumors as early as p53 KO mice.
that 4KR p53 still has some inhibitory function on tumors, which can delay tumor occurrence.
, in mice with MDM2 KO, mice died during embryonic periods due to overactivation of p53.
if KO MDM2 is also KO p53, the embryo death can be reversed.
but 4KR mice could only partially repair the embryos brought to death by MDM2 KO.
also reflects that the 4KR p53 still has some features.
so what mechanism can p53 use to suppress tumors besides iron death? The author further analyzed the possible acetylation of p53 and successfully found that p53 139 bits of lysine (corresponding to 136 bits of mice) could occur acetylation modification.
KR mutation in mice p53,136 on a 4KR basis, resulting in 5KR mice producing 100% tumors before 50 weeks.
the results were very close to p53 KO mice.
and 5KR mice were largely error-expected to die from embryos.
suggests that 139 bits of acetylation are the ultimate key to regulating p53 to suppress tumors and cause embryo death.
then what mechanism does 139-bit acetylation work? Further studies show that acetylation at 139-bit points plays an important role in p53 suppressing the mTOR path.
p53 inhibits the mTOR pathway in a variety of ways, including inducing the SESTRIN family proteins SENS1 and SENS2, and activating DDIT4 (also known as REDD1) as two important pathways.
, 5KR p53 loses the ability to activate these genes relative to 4KR, thus no longer suppressing the mTOR path.
further response experiments, in p53 5KR and KO mice, by adding the mTOR inhibitor rapamycin to the rat grain, it was able to effectively slow the occurrence of tumors in mice.
, the research continues and develops the research direction of Professor Gu Wei's laboratory for more than ten years.
the importance of regulating iron death and mTOR pathps for p53 anti-cancer function.
addition, iron death is essentially a metabolic cell death form, it can be seen that p53 for tumor metabolism regulation is an indispensable part of its anti-cancer function.
So far, Professor Gu Wei's team has successfully analyzed the function of p53, which is probably the most important anti-cancer gene, through layer-by-layer anatomical analysis, providing a theoretical basis for targeted treatment of p53 path, especially in p53-mutated tumors.
Wei, who graduated from Peking University in 1986, received his Ph.D. from Columbia University in 1995 and has been a full professor at Columbia University Medical Center since 2007 and Abraham and Mildred Goldstein Professor at Columbia University's Irvine Cancer Center.
GuWei is mainly engaged in p53 in tumor suppression and aging research.
has made outstanding achievements in the field of p53-related regulatory path (acetylation and de-ubiminization) and has published more than 50 papers in international authoritative journals such as Cell, Nature, Science, Science, Nature Biol, Molecular Cell and Cell Metab. With 14 papers published by correspondents in Cell (7), Nature (6) and Science (1), the papers were cited 38,844 times and served as a special reviewer for international authoritative journals such as Cell, Nature, Science and PNAS.
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