Disease relevance of RRM2B

• Here, we investigate the role of p53R2 in cancer invasion and metastasis [1].
• We investigated p53R2 mRNA expression in human oral normal epithelium, epithelial dysplasias and squamous cell carcinomas (SCCs) [2].
• Novel genetic variations of the p53R2 gene in patients with colorectal adenoma and controls [3].
• A recent study reported that a point mutation (G/T) in the p53 binding sequence in a colon cancer cell line completely impaired p53R2 protein activity [3].
• To investigate the effects of high-risk human papillomavirus (HPV) oncoproteins on p53R2 expression after DNA damage, we analyzed the p53R2 protein levels in human cells ectopically expressing the HPV-16 E6 and E7 genes, and in the HPV-positive cancer cell lines SiHa, CaSki and HeLa, exposed to adriamycin or to H(2)O(2) [4].

High impact information on RRM2B

• Our results indicate that p53R2 encodes a ribonucleotide reductase that is directly involved in the p53 checkpoint for repair of damaged DNA [5].
• Induction of p53R2 in p53-deficient cells caused G2/M arrest and prevented cells from death in response to adriamycin [5].
• Inhibition of endogenous p53R2 expression in cells that have an intact p53-dependent DNA damage checkpoint reduced ribonucleotide reductase activity, DNA repair and cell survival after exposure to various genotoxins [5].
• Mammalian two-hybrid assay further indicates that the amino acids 1 to 113 of p53R2 are critical for interacting with the NH(2)-terminal region (amino acids 1-93) of p21 [6].
• These data suggest a new function of p53R2 of cooperating with p21 during DNA repair at G(1) arrest [6].

Chemical compound and disease context of RRM2B

• Silencing of the p53R2 gene by RNA interference inhibits growth and enhances 5-fluorouracil sensitivity of oral cancer cells [7].

Biological context of RRM2B

• Screening of nine exons of the p53R2 [Human Genome Organisation (HUGO) official name RRM2B] gene resulted in identification of a novel polymorphism in the 5' untranslated region, which was detected in four cases [8].
• The human ribonucleotide reductase subunit hRRM2 complements p53R2 in response to UV-induced DNA repair in cells with mutant p53 [9].
• An increase in p53R2 expression by gene transfection significantly reduced the cellular invasion potential to 54% and 30% in KB and PC-3 cells, respectively, whereas inhibition of p53R2 by short interfering RNA resulted in a 3-fold increase in cell migration [1].
• CONCLUSIONS: Opposite regulation of hRRM2 and p53R2 in invasion potential might play a critical role in determining the invasion and metastasis phenotype in cancer cells [1].
• p53R2-dependent pathway for DNA synthesis in a p53-regulated cell cycle checkpoint [10].

Anatomical context of RRM2B

• In contrast, hRRM2 was up-regulated by UV in both PC3 cells and KB cells. hRRM2 and p53R2 mRNA levels were assessed by Northern blot, and the results paralleled that of the Western blot [9].
• The decrease of p53R2 is associated with cell invasion potential, which was observed in both p53 wild-type (KB) and mutant (PC-3 and Mia PaCa-2) cell lines [1].
• Ectopic expression of E6 impaired p53 and p53R2 induction after DNA damage in human fibroblasts [4].
• Moreover, SiHa, CaSki and HeLa cells were unresponsive to H(2)O(2) exposure, and adriamycin induced p53R2 levels only in SiHa cells [4].
• In cell-free systems, p53R2 did not oxidize a reactive oxygen species (ROS) indicator carboxy-H2DCFDA, but another class I RR small subunit, hRRM2, did [11].

Associations of RRM2B with chemical compounds

• To the contrary, p53R2 was 2.50-fold less sensitive than hRRM2 to the radical scavenger hydroxyurea, whereas EPR showed similar spectra of the tyrosyl radical in two proteins [12].
• Triapine, a new RR inhibitor, was equally potent for p53R2 and hRRM2 [12].
• Of interest, p53R2 was 158-fold more susceptible to the iron chelator deferoxamine mesylate than hRRM2, although the iron content of the two proteins determined by atomic absorption spectrometer was almost the same [12].
• No significant change in the expression of RRM2 was observed in either cell line, although both gemcitabine-resistant cell lines had an approximate 3-fold increase in p53R2 protein [13].
• Ectopic expression of p53R2 partially reversed the cytotoxicity of cisplatin but not that of RNR inhibitors to R2 knockdown cells [14].

Physical interactions of RRM2B

• Our results suggest that wild-type p53 directly interacts with both p53R2 and hRRM2 [15].
• These results suggest that PC3 cells are deficient in both transcription of p53R2 and binding to hRRM1 in response to UV irradiation [9].

Regulatory relationships of RRM2B

• Wild-type p53 regulates human ribonucleotide reductase by protein-protein interaction with p53R2 as well as hRRM2 subunits [15].

Other interactions of RRM2B

• Therefore, the direct interaction of p53 with p53R2 and hRRM2 and the nuclear accumulation of RR subunits after UV exposure might play a pivotal role in DNA repair [15].
• Thus, we hypothesize that hRRM2 complements p53R2 to form RR holoenzyme and maintain RR activity in PC3 cells after UV treatment [9].
• RR consists of two subunits, hRRM1 and hRRM2. p53R2 is a new RR family member [9].
• In a site-directed mutagenesis study, antioxidant activity was abrogated in p53R2 mutants Y331F, Y285F, Y49F, and Y241H, but not Y164F or Y164C [11].
• Further studies showed that purified recombinant p53R2 protein has catalase activity, which breaks down H2O2 [11].

Analytical, diagnostic and therapeutic context of RRM2B

• Confocal microscopy further confirmed that these findings were not due to translocation of hRRM2 and p53R2 from the cytoplasm to the nucleus [9].
• EXPERIMENTAL DESIGN: The immunohistochemistry was conducted on a tissue array including 49 primary and 59 metastatic colon adenocarcinoma samples to determine the relationship between p53R2 expression and metastasis [1].
• Then, p53R2 was identified by in situ hybridization to visualize and localize the expression of specific mRNAs [2].
• Additionally, we determined the frequency of these p53R2 variants in a recently concluded case-control study of incident sporadic colorectal adenomas (163 cases and 210 controls) [3].
• METHODS: We screened the p53R2 gene coding regions and a regulatory region which contains a p53 binding sequence in 100 patients with colorectal adenoma and 100 control subjects using PCR, cold SSCP, and direct DNA sequencing [3].

References