title: Transforming growth factor-beta1 inhibits all-trans retinoic acid-induced apoptosis.
abstract: The interaction between retinoids and transforming growth factor-beta1 (TGF-beta1) leading to regulation of proliferation, differentiation and apoptosis is not still fully understood. In this study, we demonstrated that a combination treatment with all-trans retinoic acid (ATRA) and TGF-beta1 led to the enhancement of ATRA-induced suppression of cell proliferation, which is accompanied by inhibition of ATRA-induced apoptosis in human leukemia HL-60 cells. This effect was preceded by the arrest of cells in G0/G1 cell cycle phase linked with pRb protein dephosphorylation, continuous accumulation of p21 and transiently increased level of p27, inhibitors of cyclin-dependent kinases. Inhibition of ATRA-induced apoptosis by TGF-beta1 was associated with an increased level of Mcl-1 protein, an anti-apoptotic member of Bcl-2 family, but not with inhibition of mitochondrial membrane depolarization. Levels of other Bcl-2 family proteins (Bcl-2, Bcl-X(L), Bad, Bak, Bax) were unaffected by simultaneous ATRA and TGF-beta1 treatment, when compared to ATRA alone. Upregulation of c-FLIP(L) protein, an inhibitor of apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), correspond with inhibition of ATRA-induced (autocrine TRAIL-mediated) caspase-8 activation and apoptosis. These results suggest that apoptosis inhibition associated with proliferation block could depend on modulation of the TRAIL apoptotic pathway and regulation of the Mcl-1 protein level. In summary, we demonstrate that the balance of processes leading to regulation of proliferation and differentiation of myeloid cells can modulate cell sensitivity to apoptosis-inducing stimuli.
authors.affiliation: Laboratory of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, 612 65 Brno, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Soucek
authors.forename: Jirí
authors.initials: J
authors.lastname: Pacherník
authors.forename: Lukás
authors.initials: L
authors.lastname: Kubala
authors.forename: Jan
authors.initials: J
authors.lastname: Vondrácek
authors.forename: Jirina
authors.initials: J
authors.lastname: Hofmanová
authors.forename: Alois
authors.initials: A
authors.lastname: Kozubík
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism / Q000494:pharmacology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D039481:CD11b Antigen / Q000096:biosynthesis / Q000187:drug effects; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000494:pharmacology; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014212:Tretinoin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D039481:CD11b Antigen; C493956:CDKN1A protein, human; C506386:CFLAR protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D016160:Retinoblastoma Protein; C508960:TGFB1 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D014212:Tretinoin; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases