Biochemical and molecular events controlled by lymphokine growth factors.
The polypeptide hormones that govern the proliferation and differentiation of the mature immune system and hematopoiesis are collectively referred to as lymphokines. We have examined a number of biochemical and molecular events stimulated by several unique lymphokines that exhibit proliferative activity on lymphoid and myeloid cell lines. IL-2 and several members of the colony-stimulating factors (multi-CSF, G-CSF, and GM-CSF) stimulate a similar pattern of cellular phosphorylation, including the prominent phosphorylation of a 68-kD substrate present in numerous distinct lineage cell lines. The 68-kD substrate is phosphorylated by protein kinase C on threonine residues and is primarily cytosolic. Another kinase system activated by either physiological ligand or synthetic diacylglycerol phosphorylated the 40S ribosomal S6 protein in a dose-dependent manner. The increased phosphorylation of S6 protein was associated with enhanced chain elongation in vitro. The kinase responsible for the in situ phosphorylation, however, was not protein kinase C but another physicochemically distinct Mg++-dependent enzyme (termed S6 kinase). These studies suggested that although protein kinase C was activated by diacylglycerol, another kinase, S6 kinase, was the effector enzyme involved in the phosphorylation of the 40S protein. IL-2 and all other lymphokines tested stimulated the transcription of the nuclear protooncogenes c-fos, c-myc, and c-myb, as well as a member of the heat shock family of proteins, HSP 70. Phorbol esters also stimulated similar gene expression; however, cAMP analogue inhibited phorbol ester- or ligand-induced c-myc expression. cAMP agonists are antiproliferative to all the growth factors tested.
Farrar
W L
WL
Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, Maryland.
Harel-Bellan
A
A
Ferris
D K
DK
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D008222:Lymphokines / Q000494:pharmacology / Q000502:physiology*
D006133:Growth Substances; D008222:Lymphokines