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

p53R2 is a p53-inducible ribonucleotide reductase subunit involved in deoxyribonucleotide biosynthesis and DNA repair. Although p53R2 has been linked to human cancer, its role in cervical cancer remains unknown. In this study, we investigated the expression and clinical significance of p53R2 in early-stage cervical cancer. p53R2 expression is significantly upregulated at both mRNA and protein levels in cervical cancer cells and tissues, compared with that in matched normal cervical cells and tissues, respectively. p53R2 overexpression is associated with increased risk of pelvic lymph node metastasis (PLNM, p = 0.001) and cancer relapse (p = 0.009). Patients with high p53R2 expression have a shorter overall survival (OS) and disease-free survival (DFS). p53R2 is an independent factor for predicting OS and DFS of cervical cancer patients. We further show that p53R2 is important for oncogenic growth, migration and invasion in cervical cancer cells. Mechanistically, p53R2 promotes Akt signaling and epithelial-mesenchymal transition (EMT). In conclusion, our study demonstrates for the first time that p53R2 protein is overexpressed in early-stage cervical cancer and unravels some unconventional oncogenic functions of p53R2. p53R2 may be a useful prognostic biomarker and therapeutic target for cervical cancer.
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PMID:p53R2 overexpression in cervical cancer promotes AKT signaling and EMT, and is correlated with tumor progression, metastasis and poor prognosis. 2865 99

Colorectal cancer (CRC) ranks as the third-leading cause of cancer-associated mortalities in Taiwan. The expression of ribonucleotide reductase M2 (RRM2) and p53R2 is associated with tumoral malignancy and progression in several types of cancer. The aim of the present study was to determine the association of p53R2/RRM2 with the upstream expression of microRNA (miR)-211 and the association of expression levels of p53, APC and k-ras with clinical outcomes in patients with CRC. The study consisted of 192 tumor tissue samples obtained from patients with CRC. Immunohistochemistry and direct sequencing of DNA were performed to analyze p53R2/RRM2 protein expression and p53/APC/k-ras gene mutations in these samples. The expression level of miR-211 was detected by reverse transcription-quantitative polymerase chain reaction. The results showed that the expression of p53R2 was lower and that of RRM2 was higher in patients with lymph node metastasis, distant metastasis, and late-stage CRC compared with patients without lymph node metastasis, distant metastasis and early-stage CRC. A high expression of RRM2 in patients had a negative effect on overall survival (OS) and disease-free survival (DFS) in CRC. Positive expression of RRM2 was detected in tumor tissues, and expression associated with the presence of k-ras gene mutation. Furthermore, it was detected that the upstream miR-211 expression was negatively associated with RRM2 expression in tumor tissues of patients with CRC. miR-211 expression was associated with survival and tumoral recurrence in patients with k-ras mutations. The present authors suggest that the downregulation of miR-211 and overexpression of RRM2 in tumor tissues of patients with CRC could be used to predict metastases and disease prognosis, particularly in patients with k-ras gene mutations.
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PMID:miR-211 regulates the expression of RRM2 in tumoral metastasis and recurrence in colorectal cancer patients with a k-ras gene mutation. 2973 18

Human lung cancer H1299 (p53-null) cells often display enhanced susceptibility to chemotherapeutics comparing to A549 (p53-wt) cells. However, little is known regarding to the association of DNA damage-response (DDR) pathway heterogeneity with drug sensitivity in these two cells. We investigated the DDR pathway differences between A549 and H1299 cells exposed to 8-chloro-adenosine (8-Cl-Ado), a potential anticancer drug that can induce DNA double-strand breaks (DSBs), and found that the hypersensitivity of H1299 cells to 8-Cl-Ado is associated with its DSB overaccumulation. The major causes of excessive DSBs in H1299 cells are as follows: First, defect of p53-p21 signal and phosphorylation of SMC1 increase S phase cells, where replication of DNA containing single-strand DNA break (SSB) produces more DSBs in H1299 cells. Second, p53 defect and no available induction of DNA repair protein p53R2 impair DNA repair activity in H1299 cells more severely than A549 cells. Third, cleavage of PARP-1 inhibits topoisomerase I and/or topoisomerase I-like activity of PARP-1, aggravates DNA DSBs and DNA repair mechanism impairment in H1299 cells. Together, DDR pathway heterogeneity of cancer cells is linked to cancer susceptibility to DNA damage-based chemotherapeutics, which may provide aid in design of chemotherapy strategy to improve treatment outcomes.
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PMID:DNA Damage-Response Pathway Heterogeneity of Human Lung Cancer A549 and H1299 Cells Determines Sensitivity to 8-Chloro-Adenosine. 2984 66

The tumor suppressor p53 acts as a transcription factor recognizing diverse DNA response elements (REs). Previous structural studies of p53-DNA complexes revealed non-canonical Hoogsteen geometry of A/T base pairs at conserved CATG motifs leading to changes in DNA shape and its interface with p53. To study the effects of DNA shape on binding characteristics, we designed REs with modified base pairs "locked" into either Hoogsteen or Watson-Crick form. Here we present crystal structures of these complexes and their thermodynamic and kinetic parameters, demonstrating that complexes with Hoogsteen base pairs are stabilized relative to those with all-Watson-Crick base pairs. CATG motifs are abundant in p53REs such as GADD45 and p53R2 related to cell-cycle arrest and DNA repair. The high-resolution structures of these complexes validate their propensity to adopt the unique Hoogsteen-induced structure, thus providing insights into the functional role of DNA shape and broadening the mechanisms that contribute to DNA recognition by proteins.
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PMID:New Insights into the Role of DNA Shape on Its Recognition by p53 Proteins. 3018 78

Doxorubicin is a widely used chemotherapeutic agent that causes dose-dependent cardiotoxicity in a subset of treated patients, but the genetic determinants of this susceptibility are poorly understood. Here, we report that a noncanonical tumor suppressor activity of p53 prevents cardiac dysfunction in a mouse model induced by doxorubicin administered in divided low doses as in the clinics. While relatively preserved in wild-type (p53 +/+ ) state, mice deficient in p53 (p53 -/- ) developed left ventricular (LV) systolic dysfunction after doxorubicin treatment. This functional decline in p53 -/- mice was associated with decreases in cardiac oxidative metabolism, mitochondrial mass, and mitochondrial genomic DNA (mtDNA) homeostasis. Notably, mice with homozygous knockin of the p53 R172H (p53 172H/H ) mutation, which like p53 -/- state lacks the prototypical tumor suppressor activities of p53 such as apoptosis but retains its mitochondrial biogenesis capacity, showed preservation of LV function and mitochondria after doxorubicin treatment. In contrast to p53-null state, wild-type and mutant p53 displayed distinct mechanisms of transactivating mitochondrial transcription factor A (TFAM) and p53-inducible ribonucleotide reductase 2 (p53R2), which are involved in mtDNA transcription and maintenance. Importantly, supplementing mice with a precursor of NAD+ prevented the mtDNA depletion and cardiac dysfunction. These findings suggest that loss of mtDNA contributes to cardiomyopathy pathogenesis induced by doxorubicin administered on a schedule simulating that in the clinics. Given a similar mtDNA protection role of p53 in doxorubicin-treated human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, the mitochondrial markers associated with cardiomyopathy development observed in blood and skeletal muscle cells may have prognostic utility.
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PMID:p53 prevents doxorubicin cardiotoxicity independently of its prototypical tumor suppressor activities. 3148 12

RRM2B gene encodes ribonucleoside-diphosphate reductase subunit M2 B, the p53-inducible small subunit (p53R2) of ribonucleotide reductase (RNR), an enzyme catalyzing dNTP synthesis for mitochondrial DNA. Defects in this gene may cause severe mitochondrial disease affecting mainly the nervous system. This study is aimed at examining the effect of deleterious nonsynonymous SNP (nsSNP) on the structure of the RRM2B protein, using a variety of prediction tools followed by a molecular modeling analysis. After using 13 algorithms, 19 nsSNPs were predicted deleterious. Among these variants, 18 decreased the protein stability and 16 were localized in very highly conserved regions. Protein 3D structure analysis showed that 18 variants changed amino acid interactions. These results concur with what has been found in experimental trials; 7 deleterious nsSNPs were previously reported in patients suffering from genetic disorders affecting the nervous system. Thus, our study will provide useful information to design more efficient and fast genetic tests to find RRM2B gene mutations.
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PMID:Prediction of the Impact of Deleterious Nonsynonymous Single Nucleotide Polymorphisms on the Human RRM2B Gene: A Molecular Modeling Study. 3277 40


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