title: In vivo erythroid recovery following paclitaxel injury: correlation between GATA-1, c-MYB, NF-E2, Epo receptor expressions, and apoptosis.
abstract: Paclitaxel (Px) is a cancer chemotherapeutic agent that causes bone marrow (BM) cytotoxicity by microtubule stabilization and by modifications in the expression of several genes. Hematopoietic progenitors show severe alterations following Px injury. Erythropoietic recovery should be accompanied by changes in the expression of transcription factors such as c-MYB, GATA-1, NF-E2, Bcl-x(L), and erythropoietin receptor (Epo-R). The aim of this work was to study the in vivo recovery of erythropoiesis and to correlate transcription factors, Bcl-x(L), and Epo-R expressions to apoptosis and changes in proliferation of murine erythroid progenitors following a single dose of Px (29 mg/kg, i.p.). BM total and differential cellularities, apoptosis (TdT-mediated dUTP Nick-End Labeling [TUNEL] assay), clonogenic assays, and immunoblots for transcription factors, Epo-R, and Bcl-x(L) were performed each day for 5 days post-injury. Apoptosis (24 +/- 0.81%, P < 0.01), inhibition of colony growth (burst-forming units-erythroid [BFU-E] and granulocyte-erythroid-macrophage [GEM]), and decrease in BM cellularities (28 +/- 4.2% of control) were maximal at 24 h following Px. The highest apoptosis was concomitant with the lowest BM cellularities. Apoptosis returned to normal values (3.08 +/- 0.61%) by day 3 post-Px. Up-regulation of c-MYB, GATA-1, Epo-R, and Bcl-x(L) expressions were observed between 24 and 48 h following Px. Correlations among c-MYB, GATA-1, Bcl-x(L), and Epo-R were extremely significant. Maximal expression of NF-E2 was observed on day 3 concomitant with the rise (threefold) of early erythroid precursors (BFU-E). Thus, cells that survive injury seem to be stimulated to produce early (24-48 h) erythroid-related and antiapoptotic proteins. Therefore, the results suggest an in vivo interplay between specific transcription factors and Bcl-x(L) during progenitor cell survival and proliferation; mechanisms triggered to restore size and composition of the erythroid compartment.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Northeast National University, Moreno 1240 (3400), Corrientes, Argentina.
authors.forename: M M
authors.initials: MM
authors.lastname: Romero-Benitez
authors.forename: M V
authors.initials: MV
authors.lastname: Aguirre
authors.forename: J A
authors.initials: JA
authors.lastname: Juaristi
authors.forename: M A
authors.initials: MA
authors.lastname: Alvarez
authors.forename: J-M
authors.initials: JM
authors.lastname: Trifaró
authors.forename: N C
authors.initials: NC
authors.lastname: Brandan
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000187:drug effects; D002470:Cell Survival; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000187:drug effects; D050981:Erythroid-Specific DNA-Binding Factors; D004920:Erythropoiesis / Q000187:drug effects*; D005260:Female; D050982:GATA1 Transcription Factor; D015870:Gene Expression / Q000187:drug effects; D019940:Genes, bcl-1 / Q000235:genetics; D020570:Genes, myb / Q000235:genetics*; D007091:Image Processing, Computer-Assisted; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D007700:Kinetics; D051379:Mice; D050983:NF-E2 Transcription Factor; D050984:NF-E2 Transcription Factor, p45 Subunit; D017239:Paclitaxel / Q000633:toxicity*; D017467:Receptors, Erythropoietin / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D050983:NF-E2 Transcription Factor; D050984:NF-E2 Transcription Factor, p45 Subunit; C494693:Nfe2 protein, mouse; D017467:Receptors, Erythropoietin; D014157:Transcription Factors; D017239:Paclitaxel