Disease relevance of RRM1

• RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer [1].
• In a multivariate analysis, high RRM1 expression was predictive of long survival independent of tumor stage, performance status, and weight loss [1].
• RRM1-induced metastasis suppression through PTEN-regulated pathways [2].
• Taq1 digestion of PCR products revealed that both alleles were transcribed in all samples where both were present at the genomic level, indicating that the RRM1 locus is not subjected to imprinting in Wilms' tumour or hepatoblastoma [3].
• In RRM1 transgenic human lung and colon cancer cell lines, we observed induction of G(2) cell cycle arrest, apoptosis, and efficient DNA damage repair [4].

High impact information on RRM1

• It is composed of two different dimeric proteins R1 and R2 (refs 3-5) [5].
• Consistent with such a requirement, a double point-mutation in RRM1 of SF2/ASF that impairs RNA binding prevents the protein from shuttling [6].
• Kid cleaves specific mRNAs at UUACU sites to rescue the copy number of plasmid R1 [7].
• The non- consensus RRM1 and the C-terminal glutamine-rich (Q) domain are required for association with U1 snRNP and to facilitate its recruitment to 5' ss [8].
• Remarkably, no characterisitc of the ventricular tachycardia including beats per episode, episodes per day, rate, prematurity index (RR1/QT) of the initiating beat, or the occurrence of associated arrhythmias was important prognostically [9].

Chemical compound and disease context of RRM1

• In the present study, we have examined the potential correlation and predictive value of ERCC1, RRM1, and XPD mRNA expression in resected specimens from 67 stage IIB, IIIA, and IIIB non-small cell lung cancer patients treated with neoadjuvant gemcitabine/platinum followed by surgery [10].
• We carried out three different studies examining individually the role of ERCC1, RRM1, and then both, mRNA expression in paraffin-embedded pretreatment bronchial biopsies from gemcitabine/cisplatin-treated advanced non-small-cell lung cancer (NSCLC) patients [11].
• In common with herpesviruses in the Varicellovirus genus of the alphaherpesvirus subfamily, FHV-1 RR1 lacks the N-terminal serine threonine protein kinase region present in herpes simplex virus (HSV)-1 and -2 [12].
• The large subunit of the herpes simplex virus type 2 (HSV-2) ribonucleotide reductase (RR1) is demonstrated to possess serine/threonine-specific kinase activity [13].
• EVM053 also exhibits a novel cis-proline (Pro53) in a loop that has been shown to contribute to R1-binding in Escherichia coli Grx-1 [14].

Biological context of RRM1

• PURPOSE: RRM1 has important functions in the determination of the malignant phenotype [1].
• Here, we show that overexpression of RRM1 in human and mouse lung cancer cell lines induced PTEN expression, reduced phosphorylation of focal adhesion kinase (FAK), suppressed migration, invasion, and metastasis formation, and increased survival in an animal model [2].
• Increased PTEN expression was required for the RRM1-induced suppression of cell motility and FAK phosphorylation [2].
• Southern blot analysis of rodent x human somatic cell hybrid DNAs confirmed the assignment of RRM1 to the short arm of human chromosome 11 [15].
• A third region, at 11p13-15 between WT1 and RRM1, was also affected by LOH [16].

Anatomical context of RRM1

• However, only the increased expression of ribonucleotide reductase subunit 1 (RRM1), which appeared in both resistant cell lines, met predefined analysis criteria for genes to investigate further [17].
• UV irradiation of serum-starved, G0/G1-enriched mouse fibroblasts, stably transformed with an R1 promoter-luciferase reporter gene construct, caused a 3-fold increase in luciferase activity 24 h after irradiation, paralleled by an increase in the levels of R1 protein [18].
• A methotrexate-resistant subline, CCRF-CEM/R1, was selected stepwise from the human leukemic lymphoblast T-cell line, CCRF-CEM, and maintained in 0.2 microM methotrexate [19].
• In contrast, UK117,026 was a more potent inhibitor of 5 alpha-reductase activity in the prostate cancer cell lines and in COS cells expressing 5 alpha R1 [20].
• AR and 5 alpha R1 mRNAs were expressed in all portions of the hair follicle [21].

Associations of RRM1 with chemical compounds

• The results from this study indicate that the level of RRM1 may affect gemcitabine response [17].
• RRM1 levels influenced time to progression (P=0.05) and even more so, survival (P=0.0028) in the gemcitabine/cisplatin arm [22].
• PSF comprises an N-terminal proline- and glutamine-rich domain, two RRMs (RRM1 and RRM2), and a C-terminal region that contains two nuclear localization signals, both of which are required for complete nuclear localization [23].
• The present study also showed that the substitutions of glutamic acid at 42 for aspartic acid and leucine at 44 for phenylalanine in the first potent alpha-helix structure of RRM1, as were seen in another ELAV-like protein Hel-N1, markedly affected the RNA binding [24].
• RRM1 Modulated In Vitro and In Vivo Efficacy of Gemcitabine and Platinum in Non-Small-Cell Lung Cancer [25].
• We detected significant differences in response rates to gemcitabine-based chemotherapy according to the allelotypes of the RRM1 promoter sequence, which could be determined using the germline DNA [26].

Physical interactions of RRM1

• These results suggest that PC3 cells are deficient in both transcription of p53R2 and binding to hRRM1 in response to UV irradiation [27].
• By using a new technique termed Gas-phase Electrophoretic-Mobility Macromolecule Analysis (GEMMA), we have found that the ATP/dATP-induced R1 oligomers have a defined size (hexamers) and can interact with the R2 dimer to form an enzymatically active protein complex (alpha(6)beta(2)) [28].

Enzymatic interactions of RRM1

• In cells infected with HSV-1 or HSV-2, RR1 had auto- and transphosphorylating activity for the small subunit of HSV ribonucleotide reductase (RR2) and immunoglobulin G (IgG) [29].

Regulatory relationships of RRM1

• Peptidomimetic inhibitors that mimic the C-terminal amino acids of R2 inhibit HSV RR by preventing the association of R1 and R2 [30].

Other interactions of RRM1

• RESULTS: RRM1 expression was significantly correlated with PTEN and RRM2 expression in tumor tissue [1].
• Patients with high levels of expression lived longer and had disease recurrence later than patients with low levels of RRM1 and PTEN [1].
• RR consists of two subunits, hRRM1 and hRRM2. p53R2 is a new RR family member [27].
• We conclude that RRM1 functions as a metastasis suppressor gene through induction of PTEN expression [2].
• The predictive value of beta-tubulin III, stathmin and RRM1 should be tested in prospective customized chemotherapy trials, the results of which will help tailor chemotherapy to improve patient survival [22].

Analytical, diagnostic and therapeutic context of RRM1

• Quantitative PCR analysis demonstrated H358-G200 cells had a greater than 125-fold increase in RRM1 RNA expression [17].
• Western blot analysis confirmed high levels of RRM1 protein in this line compared with the gemcitabine-sensitive parent [17].
• RRM1 and PTEN expression in tumor tissue was highly predictive of overall (P =.011 and.018, respectively) and disease-free survival (P =.002 and.026, respectively) [1].
• We analyzed RRM1 and ERCC1 mRNA expression in paraffin-embedded samples obtained from bronchoscopy by real-time quantitative reverse transcription-PCR [31].
• Restriction mapping by pulsed-field electrophoresis indicates that GOK is located 1.7 kb telomeric of RRM1, and both genes are transcribed in the same direction [32].

References