title: Myeloid leukemia factor 1 interfered with Bcl-XL to promote apoptosis and its function was regulated by 14-3-3.
abstract: Myeloid leukemia factor 1 (MLF1) was involved in t(3;5) chromosomal rearrangement and aberrantly expressed in myelodysplastic syndromes/acute myeloid leukemia patients. Ex vivo experiments showed that the lymphocytes from the Mlf1-deficient mice were more resistant to apoptotic stimulations than the wild-type cells. Furthermore, the ectopically expressed MLF1 induced apoptosis in the cell models. These findings revealed that MLF1 was required for the cells to respond to the apoptotic stimulations. Ex vivo experiments also demonstrated that cytokine withdrawal significantly up-regulated Mlf1's expression and promoted its association with B cell lymphoma-extra large (Bcl-XL) in the lymphocytes, at the same time reduced the association of Bax with Bcl-XL The same effects were also observed in the cells that over-expressed MLF1. However, these effects were observed in Mlf1 null lymphocytes as well as the cells over-expressing Bcl-XL. In addition, MLF1's proapoptosis could be completely prevented by co-expression of Bcl-XL and significantly attenuated in Bax/Bak double null cells. These data, taken together, strongly suggested that in response to the stresses, up-regulated Mlf1 promoted its association with Bcl-XL and reduced the available Bcl-XL for associating with Bax, which resulted in releasing Bax from the Bcl-XL and apoptosis in turn. Lastly, we showed that MLF1 was negatively regulated by 14-3-3 and revealed that 14-3-3 bound to MLF1 and physically blocked MLF1's Bcl-2 homology domain 3 (BH3) as well as Bcl-XL from associating with MLF1. Our findings suggested that ectopically expressed MLF1 could be responsible for the pathological apoptosis in early myelodysplastic syndrome (MDS) patients.
authors.affiliation: Department of Hematology, Shijiazhuang City First Hospital, 36 FanXiLu, Shijiazhuang, 050011, People's Republic of China. yisun456@yahoo.com.|Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. yisun456@yahoo.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Hematology, Shijiazhuang City First Hospital, 36 FanXiLu, Shijiazhuang, 050011, People's Republic of China.
authors.forename: Amina
authors.initials: A
authors.lastname: Fu
authors.affiliation: Department of Chemistry, University of Louisiana at Lafayette, Lafayette, LA, 70504, USA.
authors.forename: Wu
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Biochemistry, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Jyh-Rong
authors.initials: JR
authors.lastname: Chao
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Moshiach
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Morris
mesh_terms: D048948:14-3-3 Proteins / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D018797:Cell Cycle Proteins; D002470:Cell Survival; D004268:DNA-Binding Proteins; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000502:physiology*; D060168:Thymocytes / Q000502:physiology / Q000528:radiation effects; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C484412:Mlf1 protein, mouse; D011506:Proteins; D051020:bcl-X Protein
keywords: Apoptosis; BAX; Bcl-XL; Knockout; Myeloid leukemia factor 1