title: Survival factor withdrawal-induced apoptosis of TF-1 cells involves a TRB2-Mcl-1 axis-dependent pathway.
abstract: Tribbles, an atypical protein kinase superfamily member, coordinates cell proliferation, migration, and morphogenesis during the development of Drosophila and Xenopus embryos. Although Tribbles are highly conserved throughout evolution, the physiological functions of mammalian Tribbles family remain largely unclear. Here we report that human TRB2 is a pro-apoptotic molecule that induces apoptosis of cells mainly of the hematopoietic origin. TRB2 mRNA is selectively induced by removal of granulocyte macrophage colony-stimulating factor (GM-CSF) or interleukin-2 from human erythroleukemia-derived TF-1 cell line or activated primary CD4(+) T cells, respectively. It is, however, not induced by many other treatments that trigger apoptosis of these two cell types. Overexpression of TRB2 activates many apoptotic events observed in GM-CSF-deprived TF-1 cells, including loss of mitochondrial membrane potential, Mcl-1 cleavage/degradation, and activation of Bax and a number of caspases. Specific knockdown of TRB2 significantly suppresses GM-CSF deprivation-induced apoptosis and all apoptotic events mentioned above. Finally, we demonstrate that TRB2-induced cleavage and degradation of Mcl-1 are mediated via a caspase-dependent but proteasome-independent mechanism, and overexpression of Mcl-1 or its upstream activator Akt can markedly overcome the apoptogenic effect of TRB2. Altogether, these results suggest that the TRB2-Mcl-1 axis plays an important role in survival factor withdrawal-induced apoptosis of TF-1 cells.
authors.affiliation: Graduate Institute of Life Science, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Kou-Ray
authors.initials: KR
authors.lastname: Lin
authors.forename: Shern-Fwu
authors.initials: SF
authors.lastname: Lee
authors.forename: Chien-Min
authors.initials: CM
authors.lastname: Hung
authors.forename: Chung-Leung
authors.initials: CL
authors.lastname: Li
authors.forename: Hsin-Fang
authors.initials: HF
authors.lastname: Yang-Yen
authors.forename: Jeffrey J Y
authors.initials: JJ
authors.lastname: Yen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency; D006367:HeLa Cells; D006801:Humans; D007376:Interleukin-2 / Q000172:deficiency; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C515847:tribbles 2 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C489044:TRIB2 protein, human