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Article: Roscovitine Enhances All-trans Retinoic Acid (atra)-induced Leukemia Cell Differentiation: Novel Effects On Signaling Molecules For A Putative Cdk2 Inhibitor

TitleRoscovitine Enhances All-trans Retinoic Acid (atra)-induced Leukemia Cell Differentiation: Novel Effects On Signaling Molecules For A Putative Cdk2 Inhibitor
Authors
KeywordsATRA
Roscovitine
Differentiation therapy
HL-60
Lyn
Issue Date2020
PublisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/cellsig
Citation
Cellular Signalling, 2020, v. 71, p. article no. 109555 How to Cite?
AbstractAll-trans retinoic acid (ATRA)-based differentiation therapy has been unsuccessful in treating t(15;17) negative acute myeloid leukemia (AML) patients, motivating interest in combination therapies using ATRA plus other agents. Using the t (15, 17) negative HL-60 human myeloblastic leukemia model, we find that the cyclin-dependent kinase (CDK) inhibitor, roscovitine, augments signaling by an ATRA-induced macromolecular signalsome that propels differentiation and enhances ATRA-induced differentiation. Roscovitine co-treatment enhanced ATRA-induced expression of pS259- pS289/296/301- pS621-c-Raf, pS217/221-Mek, Src Family Kinases (SFKs) Lyn and Fgr and SFK Y416 phosphorylation, adaptor proteins c-Cbl and SLP-76, Vav, and acetylated 14–3-3 in the signalsome. Roscovitine enhanced ATRA-induced c-Raf interaction with Lyn, Vav, and c-Cbl. Consistent with signalsome hyper-activation, roscovitine co-treatment enhanced ATRA-induced G1/0 arrest and expression of differentiation markers, CD11b, ROS and p47 Phox. Because roscovitine regulated Lyn expression, activation and partnering, a stably transfected Lyn knockdown was generated from wt-parental cells to investigate its function in ATRA-induced differentiation. Lyn-knockdown enhanced ATRA-induced up-regulation of key signalsome molecules, c-Raf, pS259-c-Raf, pS289/296/301-c-Raf, Vav1, SLP-76, and Fgr, but with essentially total loss of pY416-SFK. Compared to ATRA-treated wt-parental cells, differentiation markers p47 phox, CD11b, G1/G0 arrest and ROS production were enhanced in ATRA-treated Lyn-knockdown stable transfectants, and addition of roscovitine further enhanced these ATRA-inducible markers. The Lyn-knockdown cells expressed slightly higher c-Raf, pS259-c-Raf, pS289/296/301-c-Raf, and SLP-76 than wt-parental cells, and this was associated with enhanced ATRA-induced upregulation of Fgr and cell differentiation, consistent with heightened signaling, suggesting that enhanced Fgr may have compensated for loss of Lyn to enhance differentiation in the Lyn-knockdown cells.
Persistent Identifierhttp://hdl.handle.net/10722/283755
ISSN
2023 Impact Factor: 4.4
2023 SCImago Journal Rankings: 1.317
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorRashid, A-
dc.contributor.authorDuan, X-
dc.contributor.authorGao, F-
dc.contributor.authorYang, M-
dc.contributor.authorYen, A-
dc.date.accessioned2020-07-03T08:23:37Z-
dc.date.available2020-07-03T08:23:37Z-
dc.date.issued2020-
dc.identifier.citationCellular Signalling, 2020, v. 71, p. article no. 109555-
dc.identifier.issn0898-6568-
dc.identifier.urihttp://hdl.handle.net/10722/283755-
dc.description.abstractAll-trans retinoic acid (ATRA)-based differentiation therapy has been unsuccessful in treating t(15;17) negative acute myeloid leukemia (AML) patients, motivating interest in combination therapies using ATRA plus other agents. Using the t (15, 17) negative HL-60 human myeloblastic leukemia model, we find that the cyclin-dependent kinase (CDK) inhibitor, roscovitine, augments signaling by an ATRA-induced macromolecular signalsome that propels differentiation and enhances ATRA-induced differentiation. Roscovitine co-treatment enhanced ATRA-induced expression of pS259- pS289/296/301- pS621-c-Raf, pS217/221-Mek, Src Family Kinases (SFKs) Lyn and Fgr and SFK Y416 phosphorylation, adaptor proteins c-Cbl and SLP-76, Vav, and acetylated 14–3-3 in the signalsome. Roscovitine enhanced ATRA-induced c-Raf interaction with Lyn, Vav, and c-Cbl. Consistent with signalsome hyper-activation, roscovitine co-treatment enhanced ATRA-induced G1/0 arrest and expression of differentiation markers, CD11b, ROS and p47 Phox. Because roscovitine regulated Lyn expression, activation and partnering, a stably transfected Lyn knockdown was generated from wt-parental cells to investigate its function in ATRA-induced differentiation. Lyn-knockdown enhanced ATRA-induced up-regulation of key signalsome molecules, c-Raf, pS259-c-Raf, pS289/296/301-c-Raf, Vav1, SLP-76, and Fgr, but with essentially total loss of pY416-SFK. Compared to ATRA-treated wt-parental cells, differentiation markers p47 phox, CD11b, G1/G0 arrest and ROS production were enhanced in ATRA-treated Lyn-knockdown stable transfectants, and addition of roscovitine further enhanced these ATRA-inducible markers. The Lyn-knockdown cells expressed slightly higher c-Raf, pS259-c-Raf, pS289/296/301-c-Raf, and SLP-76 than wt-parental cells, and this was associated with enhanced ATRA-induced upregulation of Fgr and cell differentiation, consistent with heightened signaling, suggesting that enhanced Fgr may have compensated for loss of Lyn to enhance differentiation in the Lyn-knockdown cells.-
dc.languageeng-
dc.publisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/cellsig-
dc.relation.ispartofCellular Signalling-
dc.subjectATRA-
dc.subjectRoscovitine-
dc.subjectDifferentiation therapy-
dc.subjectHL-60-
dc.subjectLyn-
dc.titleRoscovitine Enhances All-trans Retinoic Acid (atra)-induced Leukemia Cell Differentiation: Novel Effects On Signaling Molecules For A Putative Cdk2 Inhibitor-
dc.typeArticle-
dc.identifier.emailRashid, A: arashid2@hku.hk-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.cellsig.2020.109555-
dc.identifier.pmid32032659-
dc.identifier.scopuseid_2-s2.0-85082511333-
dc.identifier.hkuros310704-
dc.identifier.volume71-
dc.identifier.spagearticle no. 109555-
dc.identifier.epagearticle no. 109555-
dc.identifier.isiWOS:000528250900002-
dc.publisher.placeUnited States-
dc.identifier.issnl0898-6568-

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