Mcl-1, an early-induction molecule, modulates activin A-induced apoptosis and differentiation of CML cells.

Abstract

Activin A, one member of the transforming growth factor (TGF)-beta superfamily, is known to be a commitment factor for cell death and differentiation. In the present study, we demonstrate that human chronic myeloid leukemia (CML) cell lines, KU812 and K562 cells, either induced apoptosis or differentiation, respectively, by treatment with activin A. During these cell fate decisive events caused by activin A, rapid and transient up-regulation of Mcl-1 was observed in both cell lines. In activin A-induced apoptosis of KU812 cells, continuous up-regulation of Bax was observed. After the decrease in Mcl-1 expression had occurred, activation of caspase-9 and caspase-3 and cleavage of DFF45 were shown to take place in KU812 cells, resulting in the fragmentation of the genomic DNA of the cells. In contrast, the down-regulation of Mcl-1 without up-regulation of Bax caused accumulation of hemoglobin (Hb) contents in activin A-treated K562 cells. Interestingly, erythropoietin (EPO) prevented activin A-induced apoptosis with continuous expression of Mcl-1 and caused KU812 cells to undergo erythroid differentiation. To address the role of Mcl-1 in activin A-treated CML cells, KU812 and K562 cells were stably transfected with cDNA encoding Mcl-1 (designated as KU812/mcl and K562/mcl cells). As in combined effect of activin A and EPO on the parental KU812 cells, activin A induced differentiation, but not apoptosis, of KU812/mcl cells without modulating Bax levels. Activin A-treated K562/mcl cells, as well as parental cells, were only differentiated to erythroid cells. These results suggest that Mcl-1 is an early inducible gene activated by the activin A signaling pathway for both cellular differentiation and apoptosis, and continuous expression of Mcl-1 may be contributed to differentiation signals to the erythroid lineage in CML cells.

• Authors: Y Fukuchi, M Kizaki, K Yamato, C Kawamura, A Umezawa, Hata Ji, T Nishihara, Y Ikeda
• Journal: Oncogene (Oncogene) Vol. 20 Issue 6 Pg. 704-13 (Feb 08 2001) ISSN: 0950-9232 [Print] England
• PMID: 11314004 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Caspase Inhibitors
• Myeloid Cell Leukemia Sequence 1 Protein
• Neoplasm Proteins
• Proto-Oncogene Proteins c-bcl-2
• Activins
• Erythropoietin
• Inhibins

Topics

• Activins
• Apoptosis
• Caspase Inhibitors
• Cell Differentiation (drug effects)
• Cell Division (drug effects)
• Drug Interactions
• Erythropoietin (pharmacology)
• Inhibins (pharmacology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (pathology)
• Myeloid Cell Leukemia Sequence 1 Protein
• Neoplasm Proteins (metabolism)
• Proto-Oncogene Proteins c-bcl-2