Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical oncology is still challenged by the development of drug resistance of tumors that result in poor prognosis for patients. There is an urgent necessity to understand the molecular mechanisms of resistance and to develop novel therapy strategies. Artesunate (ART) is an anti-malarial drug, which also exerts profound cytotoxic activity towards cancer cells. We first applied a gene-hunting approach using cluster and COMPARE analyses of microarray-based transcriptome-wide mRNA expression profiles. Among the genes identified by this approach were genes from diverse functional groups such as structural constituents of ribosomes (RPL6, RPL7, RPS12, RPS15A), kinases (CABC1, CCT2, RPL41), transcriptional and translational regulators (SFRS2, TUFM, ZBTB4), signal transducers (FLNA), control of cell growth and proliferation (RPS6), angiogenesis promoting factors (ITGB1), and others (SLC25A19, NCKAP1, BST1, DBH, FZD7, NACA, MTHFD2). Furthermore, we applied a candidate gene approach and tested the role of resistance mechanisms towards established anti-cancer drugs for ART resistance. By using transfected or knockout cell models we found that the tumor suppressor p16(INK4A) and the anti-oxidant protein, catalase, conferred resistance towards ART, while the oncogene HPV-E6 conferred sensitivity towards ART. The tumor suppressor p53 and its downstream protein, p21, as well as the anti-oxidant manganese-dependent superoxide dismutase did not affect cellular response to ART. In conclusion, our pharmacogenomic approach revealed that response of tumor cells towards ART is multi-factorial and is determined by gene expression associated with either ART sensitivity or resistance. At least some of the functional groups of genes (e.g. angiogenesis promoting factors, cell growth and proliferation-associated genes signal transducers and kinases) are also implicated in clinical responsiveness of tumors towards chemotherapy. It merits further investigation, whether ART is responsive in clinically refractory tumors and whether the genes identified in the present study also determine clinical responsiveness towards ART.
 ...
PMID:Factors determining sensitivity or resistance of tumor cell lines towards artesunate. 2014 94

MDM2, a critical negative regulator of p53, is often overexpressed in leukemia, but few p53 mutations are found, suggesting that p53-independent MDM2 expression occurs due to alterations in MDM2 upstream regulators. In this study, a high MDM2 transcription level was observed (41.17%) regardless of p53 expression in patient with acute myeloid leukemia (AML). Therefore, we performed genome-scale functional screening of the human genes modulating MDM2 expression in a p53-independent manner. We searched co-expression profiles of genes showing a positive or negative pattern with MDM2 expression in a DNA microarray database, selected1089 links, and composed a screening library of 368 genes. Using MDM2 P1 and P2 promoter-reporter systems, we screened clones regulating MDM2 transcriptions in a p53-independent manner by overexpression. Nine clones from the screening library showed enhanced MDM2 promoter activity and MDM2 expression in p53-deficient HCT116 cells. Among them, six clones, including NTRK2, GNA15, SFRS2, EIF5A, ELAVL1, and YWHAB mediated MAPK signaling for expressing MDM2. These results indicate that p53-independent upregulation of MDM2 by increasing selected clones may lead to oncogenesis in AML and that MDM2-modulating genes are novel potential targets for AML treatment.
 ...
PMID:Genome-scale functional analysis of the human genes modulating p53 activity by regulating MDM2 expression in a p53-independent manner. 2752 44

As a component of p53-dependent lncRNA (long non-coding RNA), PANDAR (the promoter of CDKN1A antisense DNA damage activated RNA) participates in the epigenetic regulation in human cancer. However, the involvement of PANDAR in cancer chemoresistance is unknown. In this study, we report that PANDAR serves as a negative regulator of cisplatin sensitivity in human ovarian cancer via PANDAR-SRFS2-p53 feedback regulation in nuclear. Our data showed that among the drugs commonly used in ovarian cancer therapy, cisplatin induces higher levels of PANDAR compared with doxorubicin and paclitaxel. We also proved that PANDAR exhibited higher expression in cisplatin-resistant ovarian cancer tissues and cells, compared with cisplatin-sensitive ones, and this expression pattern depends on wild-type p53 (wt-p53), not mutant-p53 (mt-p53). In vitro and in vivo, PANDAR overexpression improved cell survival rate and tumor growth in response to cisplatin, while depletion of PANDAR leads to a reduced tumor growth. Further investigation revealed that PANDAR-reduced cisplatin sensitivity was likely or partly due to the PANDAR-binding protein SFRS2 (arginine/serine-rich 2), a splicing factor with the ability to negative regulate p53 and its phosphorylation at Serine 15 (Ser15). This feedback regulation of PANDAR-SFRS2-p53 leads to a reduced transactivation of p53-related pro-apoptotic genes, such as PUMA (p53-upregulated modulator of apoptosis). In addition, in platinum-treated patients with relapsed ovarian cancer, resistant period was positively correlated with the expression of PANDAR and SFRS2, and inversely associated with expression of p53-Ser15 and PUMA in these clinical tissues. Last but not least, the role of PANDAR in chemoresistance was confirmed in patients with ovarian cancer. These findings reveal a novel regulatory maneuver of cancer cells in response to chemostress, and might shed light on overcoming cisplatin resistance in ovarian cancer.
 ...
PMID:The cisplatin-induced lncRNA PANDAR dictates the chemoresistance of ovarian cancer via regulating SFRS2-mediated p53 phosphorylation. 3037 98