The gene expression signature of anagrelide provides an insight into its mechanism of action and uncovers new regulators of megakaryopoiesis
Jones, Paul M.
Wiley Online Library
MetadataDangos cofnod eitem llawn
BACKGROUND: Anagrelide is a cytoreductive agent used to lower platelet counts in essential thrombocythemia. Although the drug has been known to selectively inhibit megakaryopoiesis for many years, the molecular mechanism accounting for this activity is still unclear. OBJECTIVES AND METHODS: To address this issue we have compared the global gene expression profiles of human hematopoietic cells treated ex-vivo with and without anagrelide while growing under megakaryocyte differentiation conditions, using high-density oligonucleotide microarrays. Gene expression data were validated by the quantitative polymerase chain reaction and mined to identify functional subsets and regulatory pathways. RESULTS: We identified 328 annotated genes differentially regulated by anagrelide, including many genes associated with platelet functions and with the control of gene transcription. Prominent among the latter was TRIB3, whose expression increased in the presence of anagrelide. Pathway analysis revealed that anagrelide up-regulated genes that are under the control of the transcription factor ATF4, a known TRIB3 inducer. Notably, immunoblot analysis demonstrated that anagrelide induced the phosphorylation of eIF2α, which is an upstream regulator of ATF4, and increased ATF4 protein levels. Furthermore, salubrinal, an inhibitor of eIF2α dephosphorylation, increased the expression of ATF4-regulated genes and blocked megakaryocyte growth.
Journal of Thrombosis and Haemostasis
Ahluwalia M, Butcher L, Donovan H, Killick-Cole C, Jones PM, Erusalimsky JD (2015) 'The gene expression signature of anagrelide provides an insight into its mechanism of action and uncovers new regulators of megakaryopoiesis', Journal of Thrombosis and Haemostasis, 13 (6), pp. 1103–1112
Dynodwr Gwrthrych Digidol (DOI)http://dx.doi.org/10.1111/jth.12959
This article was published in Journal of Thrombosis and Haemostasis on 9 May 2015 (online), available open access at http://dx.doi.org/10.1111/jth.12959 The author's post-print was made available in this repository from 09 May 2016
HawliauCreative Commons Attribution Non-Commercial No Derivatives License
Oni nodir yn wahanol, disgrifir trwydded yr eitem hon fel a ganlyn Creative Commons Attribution Non-Commercial No Derivatives License
Yn dangos eitemau sy’n perthyn drwy deitl, awdur, pwnc a chrynodeb.
Hassan, Nurudeen; Ali, Ahmed; Withycombe, Cathryn; Ahluwalia, Maninder; Al-Nasseri, Raya Hamdan; Tonks, Alex; Morris, Keith (Elsevier, 2018-03-19)Vicenin-2, a C-glycoside flavone that is present in many plant sources, exerts potent anti-inflammatory effects in a number of cell and animal models of inflammation. Ten-eleven translocation (TET)-2 has recently gained ...
Membrane and soluble CD14 expression in response to lipopolysaccharides exposure in monocytic cell models Kwok, Eugene (Cardiff Metropolitan University, 2011)Background - CD14 is an important cell surface molecule of monocytic cells. It is involved in cellular activation in binding with bacterial endotoxin lipopolysaccharide (LPS). The receptor for lipopolysaccharide LPS (CD14) ...
Yakeu, Gertrude (University of WalesCardiff School of Health Sciences, 2010)Pharmacological activation of the nuclear receptor PPARγ enhances differentiation of circulating monocytes towards an alternative anti-inflammatory M2 phenotype, linked to atherosclerosis and its cardiovascular complications. ...