Document Detail


Efficient activation of p53 pathway in A549 cells exposed to L2, a novel compound targeting p53-MDM2 interaction.
MedLine Citation:
PMID:  19579266     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The tumor suppressor p53 plays a key role in the regulation of cell cycle, apoptosis, DNA repair, and senescence. It acts as a transcriptional factor, and is able to activate various genes to exert specific functions. MDM2, the main regulator of p53, inhibits the function of p53 through direct interaction. On the basis of this finding, inhibiting the MDM2-p53 interaction can be a potentially important target for cancer therapy. We showed here that L2, an analog of small-molecule MDM2 antagonist nutlins, stabilized p53 and selectively activated the p53 pathway in p53 wild-type A549 cells, resulting in a pronounced antiproliferation effect through inducing cell cycle arrest and apoptosis. Meanwhile, we confirmed by immunoprecipitation analysis that L2 could also inhibit MDM2-p53 interaction, similar to nutlin-1. Real-time PCR results revealed that L2 had no effect on the p53 gene transcriptional level, but it could induce the upregulation of p21 at the transcriptional level, which was the downstream of p53. Therefore, we concluded that the accumulation of p53 caused by L2 was mainly because of the decrease of the protein degradation rather than the elevation of p53 gene expression. Furthermore, no phosphor-p53 formed after L2 treatments, indicating that a genetoxic mechanism was unlikely to contribute to the activation of p53 by L2. In conclusion, the data acquired from A549 cells indicated that L2 exhibited high antiproliferation activity by disrupting MDM2-p53 interaction, and that the mechanism was derived from the activation of p53 and the p53 pathway. It was also surprising that L2 showed high antiproliferation effect against p53 null HL60 cells, which was quite different from nutlin-1. G2/M phase arrest might have contributed to the high antiproliferation activity of L2 on HL60 cells. The changes of p53 and MDM2 protein levels in L2-treated HL60 cells indicated that the mechanisms involved in the cell cycle arrest in A549 and HL60 cells were probably different, to which our future research would be devoted.
Authors:
Lei Zhang; Jun Zhang; Chunqi Hu; Ji Cao; Xinglu Zhou; Yongzhou Hu; Qiaojun He; Bo Yang
Related Documents :
9257696 - Cell cycle specificity of fas-mediated apoptosis in wil-2 cells.
12012016 - The tumour suppressor p33ing1 does not enhance camptothecin-induced cell death in melan...
8667426 - Ucn-01: a potent abrogator of g2 checkpoint function in cancer cells with disrupted p53.
12920036 - Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leuk...
11861476 - A genetic hierarchy establishes mitogenic signalling and mitotic competence in the rena...
25163766 - Ano1 (tmem16a) in pancreatic ductal adenocarcinoma (pdac).
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anti-cancer drugs     Volume:  20     ISSN:  1473-5741     ISO Abbreviation:  Anticancer Drugs     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-07-02     Completed Date:  2010-01-12     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9100823     Medline TA:  Anticancer Drugs     Country:  England    
Other Details:
Languages:  eng     Pagination:  416-24     Citation Subset:  IM    
Affiliation:
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / chemistry,  pharmacology*
Apoptosis / drug effects
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Gene Expression Regulation / drug effects
Humans
Imidazoles / chemistry,  pharmacology*
Molecular Structure
Piperazines / chemistry,  pharmacology*
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*,  genetics
Reactive Oxygen Species / metabolism
Signal Transduction / drug effects*
Tumor Suppressor Protein p53 / genetics,  metabolism*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Imidazoles; 0/L2 compound; 0/Piperazines; 0/Reactive Oxygen Species; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 0/nutlin 1; EC 6.3.2.19/MDM2 protein, human; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Structural studies on aryl-substituted enaminoketones and their thio analogues. Part I. Analysis of ...
Next Document:  The role of own-body representations in action observation: a functional MRI study.