Genetic variants predict optimal timing of radiotherapy to reduce side-effects in breast cancer patients
West, Catharine ML
AffiliationLeicester Cancer Research Centre, University of Leicester, Leicester
MetadataShow full item record
AbstractThe retinal cones of teleost fish contract at dawn and elongate at dusk. We have previously reported that we can selectively induce detergent-lysed models of cones to undergo either reactivated contraction or reactivated elongation, with rates and morphology comparable to those observed in vivo. Reactivated contraction is ATP dependent, activated by Ca2+, and inhibited by cAMP. In addition, reactivated cone contraction exhibits several properties that suggest that myosin phosphorylation plays a role in mediating Ca2+-activation (Porrello, K., and B. Burnside, 1984, J. Cell Biol., 98:2230-2238). We report here that lysed cone models can be induced to contract in the absence of Ca2+ by incubation with trypsin-digested, unregulated myosin light chain kinase (MLCK) obtained from smooth muscle. This observation provides further evidence that MLCK plays a role in regulating cone contraction. We also report here that lysed cone models can be induced to contract in the absence of Ca2+ by incubation with high concentrations of MgCl2 (10-20 mM). Mg2+-induced reactivated contraction is supported by inosine triphosphate (ITP) just as well as by ATP. Because ITP will not serve as a substrate for MLCK, this finding suggests that Mg2+-activation of contraction does not require myosin phosphorylation. Although Ca2+-induced contraction is completely blocked by cAMP at concentrations less than 10 microM, cAMP has no effect on cone contraction activated by unregulated MLCK or by high Mg2+ in the absence of Ca2+. Because trypsin digestion of MLCK cleaves off not only the Ca2+/calmodulin-binding site but also the site phosphorylated by cAMP-dependent protein kinase, and because Mg2+ activation of cone contraction circumvents MLCK action altogether, both these observations would be expected if cAMP inhibits reactivated cone contraction by catalyzing the phosphorylation of MLCK and thus reducing its affinity for Ca2+, as has been described for smooth muscle. Together our results suggest that in lysed cone models, myosin phosphorylation is sufficient for activating cone contraction, even in the absence of other Ca2+-mediated events, that cAMP inhibition of contraction is mediated by cAMP-dependent phosphorylation of MLCK, and that 10-20 mM Mg2+ can activate actin-myosin interaction to produce contraction in the absence of myosin phosphorylation.
CitationJohnson K, Chang-Claude J, Critchley AM, Kyriacou C, Lavers S, Rattay T, et al. Genetic Variants Predict Optimal Timing of Radiotherapy to Reduce Side-effects in Breast Cancer Patients. Clin Oncol. 2018 Oct 30.
- REQUITE: A prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer.
- Authors: Seibold P, Webb A, Aguado-Barrera ME, Azria D, Bourgier C, Brengues M, Briers E, Bultijnck R, Calvo-Crespo P, Carballo A, Choudhury A, Cicchetti A, Claßen J, Delmastro E, Dunning AM, Elliott RM, Fachal L, Farcy-Jacquet MP, Gabriele P, Garibaldi E, Gómez-Caamaño A, Gutiérrez-Enríquez S, Higginson DS, Johnson K, Lobato-Busto R, Mollà M, Müller A, Payne D, Peleteiro P, Post G, Rancati T, Rattay T, Reyes V, Rosenstein BS, De Ruysscher D, De Santis MC, Schäfer J, Schnabel T, Sperk E, Symonds RP, Stobart H, Taboada-Valladares B, Talbot CJ, Valdagni R, Vega A, Veldeman L, Ward T, Weißenberger C, West CML, Chang-Claude J, REQUITE consortium.
- Issue date: 2019 Sep
- Increasing the rate of late toxicity by changing the score? A comparison of RTOG/EORTC and LENT/SOMA scores.
- Authors: Hoeller U, Tribius S, Kuhlmey A, Grader K, Fehlauer F, Alberti W
- Issue date: 2003 Mar 15
- A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity.
- Authors: Barnett GC, Thompson D, Fachal L, Kerns S, Talbot C, Elliott RM, Dorling L, Coles CE, Dearnaley DP, Rosenstein BS, Vega A, Symonds P, Yarnold J, Baynes C, Michailidou K, Dennis J, Tyrer JP, Wilkinson JS, Gómez-Caamaño A, Tanteles GA, Platte R, Mayes R, Conroy D, Maranian M, Luccarini C, Gulliford SL, Sydes MR, Hall E, Haviland J, Misra V, Titley J, Bentzen SM, Pharoah PD, Burnet NG, Dunning AM, West CM
- Issue date: 2014 May
- Comparison of acute skin reaction following morning versus late afternoon radiotherapy in patients with breast cancer who have undergone curative surgical resection.
- Authors: Noh JM, Choi DH, Park H, Huh SJ, Park W, Seol SW, Jeong BK, Nam SJ, Lee JE, Kil WH
- Issue date: 2014 May
- In vitro cellular radiosensitivity in relationship to late normal tissue reactions in breast cancer patients: a multi-endpoint case-control study.
- Authors: Vandevoorde C, Depuydt J, Veldeman L, De Neve W, Sebastià N, Wieme G, Baert A, De Langhe S, Philippé J, Thierens H, Vral A
- Issue date: 2016 Dec