The Study On Regulation Of P53R175H By Apak

The tumour suppressor p53is studied completely and is also the most frequentlymutated gene in human cancer; about50%of all human cancers have mutant p53. Lossof p53function inevitably promotes tumorigenesis and also renders tumor cellsresistant to chemo-and radiotherapy. Mutants in p53is the primary cause ofLi-Fraumeni syndrome. patients acquire mutants in genome through inheritancepathway so that result in tumor in early age.p53mutations frequently occur inconserved regions of the p53DNA binding and lost the ability to meet its target genes.When p53mutation, wild-type p53lost the ability to regulate cell cycle arrest,induction of apoptosis, cell senescence mediated maintenance of genome stability,mismatch repair of DNA base tumor suppressor gene function, which is called themutant p53“loss of function”. At the same time, the mutant p53acquired cancer genefunction, such as a series of transcription of target genes accelerate the process ofcancer, enhance the chemotherapy drug resistance, to prevent the occurrence ofapoptosis in cancer cells, inhibition of p63, p73activity, this process is called“gain-of-function”. And function of mutant p53can also inhibit the activity ofwild-type p53by a dominant negative effect. It is because of these characteristics ofmutant p53, mutant p53became hot in Cancer Research. Experts prior studies havedemonstrated that p53has a lot of mutation sites, but there are several recurrentmutations in the tumor sites, we call the mutation hotspot: R175, G245, R248, R249,R273, R282. Sites175and273is the most frequently occurring mutation of the p53protein. The p53R175H of arginine at position175was mutated to histidine.mutantp53R175H is classified structure type of mutation. Mutant p53under physiologicalconditions is highly flattened state，but the mutation to a large extent will affect the p53protein folding. Further affect the stability of the p53protein, thereby changing the p53 protein function, So can exhibit a loss of function. Studies have shown that the mutantp53R175H to prevent wt p53combined with its downstream target genes therebyinhibiting the WT p53’s function, meanwhile also showed its “gain of function”. It canactivate transcription original WT p53inhibition of gene; can suppress the apoptosisby DNA damage.In earlier work, we have learned to Apak (ATM and p53associated KRAB-type zincfinger protein, also known as ZNF420). Apak belong KRAB zinc finger protein(KZNFs) family members that are involved in the inhibition of transcription of thegene. It as a negative regulator of the p53molecule, effectively inhibit p53-mediatedapoptosis, cell cycle arrest and have no obvious role in the regulation to physiologicalfunctions involved with p53. It can be selectively lowered apoptosis-related p53targetgene expression and suppress p53-mediated apoptosis. The Apak forms a complex withp53in normal cells through the KAP1raised ATM (protein kinase) and HDAC1(histone deacetylase), inhibited p53acetylation, and synergistic negative regulation ofp53function. In DNA damage conditions, ATM is activated, the phosphorylation stateof Apak is separately with p53while lifting the inhibition of p53to promote p53activation and apoptosis induced by. Lab researchers also found that Apak cancompetitively bind the p53stress components. The new find enrich the p53selectiveregulation mechanism. The researchers identified the Apak molecules is the first directtranscription of the gene p53AIP1inhibitory factor, provides the basis for theregulation of gene expression studies p53AIP1. Apak protein belongs to the largest inthe mammalian transcription factor family---KRAB zinc finger protein (also calledKZNF) family, up to more than400the number of its members, the structure is veryconservative, but each function is unclear, this study has laid a solid foundation for thestudy of the mechanism of action of the other family members.Studies show can p53R175H like wt p53,in DNA damage stress cells p53R175H canstabilize its protein levels can also be like the wt p53degraded by the HDM2(E3),so wheather p53R175H like wt p53is regulated by Apak is interesting. This study furtherresearch mutant p53R175H is regulated by Apak and improve the function mechanismof Apak. Finally, the study recognized that the Apak lose the ability to regulate andcontrol the p53R175H.