Oncogenic effects of overexpression of the interleukin-3 receptor on hematopoietic cells.
To elucidate the relationship between malignant transformation and cytokine receptor expression, the interleukin-3 receptor (IL-3R) complex was examined in an IL-3-dependent parental line and cells transformed by cytokines and oncogenes. In IL-3-dependent cells grown in medium containing optimum amounts of IL-3, the IL-3R complex was detected at low levels indicating that the receptor was down-regulated in response to IL-3. However, upon depletion of IL-3, IL-3R levels increased documenting that its expression correlated inversely with the concentration of IL-3 provided. In contrast, more IL-3 receptors were observed constitutively in autocrine-transformed derivative lines, which secreted suboptimal amounts of IL-3. To examine the effects of activated oncogenes on IL-3R expression in autocrine-transformed cells, the cells were infected with retroviral vectors containing various oncogenes. Decreased levels of IL-3R expression were observed in the oncogene-infected cells. These studies imply that important regulatory cross-talk occurs between ligands and their cognate receptors in cytokine-dependent hematopoietic cells. Deregulation of this ligand-receptor interaction in the oncogene-infected cells may be a consequence of the cells using modified signal transduction pathways which bypass the IL-3:IL-3R interaction. To determine the effects of IL-3 receptor overexpression on the cytokine dependency of hematopoietic cells, IL-3R alpha and beta cDNAs were inserted into retroviral vectors. Overexpression of either the alpha or beta chains did not directly relieve factor dependency, however, constitutive expression of the IL-3R alpha allowed the cells to proliferate in suboptimal concentrations of IL-3. Moreover, factor-independent transformants were subsequently isolated from pools of cells infected with viruses containing either the alpha or beta receptor cDNAs at a frequency of approximately 1 in 10(3) to 10(4) cells whereas such cells were not recovered from control cells. Deregulation of IL-3 receptor chain gene expression may provide a proliferative advantage to hematopoietic cells growing under conditions in which the cytokine is limiting and allow the development of a leukemia.
Steelman
L S
LS
Department of Microbiology and Immunology, East Carolina University School of Medicine, Greenville, North Carolina 27858, USA.
Algate
P A
PA
Blalock
W L
WL
Wang
X Y
XY
Prevost
K D
KD
Hoyle
P E
PE
McCubrey
J A
JA
D015152:Blotting, Northern; D015139:Blotting, Southern; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D005822:Genetic Vectors; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D009857:Oncogenes; D012333:RNA, Messenger / Q000378:metabolism; D016185:Receptors, Interleukin-3 / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics
D007377:Interleukin-3; D012333:RNA, Messenger; D016185:Receptors, Interleukin-3