The novel primary response gene MyD118 and the proto-oncogenes myb, myc, and bcl-2 modulate transforming growth factor beta 1-induced apoptosis of myeloid leukemia cells.
Cell numbers are regulated by a balance among proliferation, growth arrest, and programmed cell death. A profound example of cell homeostasis, controlled throughout life, is the complex process of blood cell development, yet little is understood about the intracellular mechanisms that regulate blood cell growth arrest and programmed cell death. In this work, using transforming growth factor beta 1 (TGF beta 1)-treated M1 myeloid leukemia cells and genetically engineered M1 cell variants, the regulation of growth arrest and apoptosis was dissected. Blocking of early expression of MyD118, a novel differentiation primary response gene also shown to be a primary response gene induced by TGF beta 1, delayed TGF beta 1-induced apoptosis, demonstrating that MyD118 is a positive modulator of TGF beta 1-mediated cell death. Elevated expression of bcl-2 blocked the TGF beta 1-induced apoptotic pathway but not growth arrest induced by TGF beta 1. Deregulated expression of either c-myc or c-myb inhibited growth arrest and accelerated apoptosis, demonstrating for the first time that c-myb plays a role in regulating apoptosis. In all cases, the apoptotic response was correlated with the level of MyD118 expression. Taken together, these findings demonstrate that the primary response gene MyD118 and the c-myc, c-myb, and bcl-2 proto-oncogenes interact to modulate growth arrest and apoptosis of myeloid cells.
Selvakumaran
M
M
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia 19104-6059.
Lin
H K
HK
Sjin
R T
RT
Reed
J C
JC
Liebermann
D A
DA
Hoffman
B
B
D000818:Animals; D000943:Antigens, Differentiation; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002455:Cell Division; D002460:Cell Line; D002999:Clone Cells; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016259:Genes, myc; D014644:Genetic Variation; D007700:Kinetics; D007942:Leukemia, Experimental; D007951:Leukemia, Myeloid; D051379:Mice; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D020598:Proto-Oncogene Proteins c-myb; D011519:Proto-Oncogenes; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020598:Proto-Oncogene Proteins c-myb; D016212:Transforming Growth Factor beta; C490125:Gadd45b protein, mouse; D000097642:GADD45 Proteins