Interleukin 3 stimulates proliferation via protein kinase C activation without increasing inositol lipid turnover.
Interleukin 3 (IL-3) is required for the survival and proliferation of the FDCP-Mix 1 multipotent stem cell line. IL-3 or phorbol esters can rapidly translocate protein kinase C from a cytosolic to a membrane-bound form in these cells. Phorbol esters were able to partially replace the requirement of FDCP-Mix 1 cells for IL-3. Down-modulation of protein kinase C levels by chronic treatment with phorbol ester markedly reduced the ability of the cells to proliferate in response to either IL-3 or phorbol esters. These data indicate that IL-3 can activate protein kinase C, leading to the survival and proliferation of stem cells. Protein kinase C is activated conventionally by complexing with diacylglycerol which accumulates in the cell membrane after agonist-stimulated hydrolysis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2]. However, there was no detectable breakdown of PtdIns(4,5)P2 when IL-3 was added to FDCP-Mix 1 cells, nor was there detectable accumulation of inositol phosphates in response to IL-3. In contrast, rapid hydrolysis of PtdIns(4,5)P2 and accumulation of inositol 1,4,5-trisphosphate was elicited by readdition of horse serum to serum-starved cells, thus indicating that these cells possess the necessary machinery to undergo agonist-mediated inositol phospholipid breakdown. We conclude that the mechanism whereby IL-3 can activate protein kinase C leading to proliferation is not associated with inositol phospholipid hydrolysis.
Whetton
A D
AD
Department of Biochemistry and Applied Molecular Biology, UMIST, Manchester, United Kingdom.
Monk
P N
PN
Consalvey
S D
SD
Huang
S J
SJ
Dexter
T M
TM
Downes
C P
CP
D029742:Caenorhabditis elegans Proteins; D002118:Calcium / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism; D002352:Carrier Proteins; D002460:Cell Line; D002470:Cell Survival; D004261:DNA Replication; D004789:Enzyme Activation; D007294:Inositol / Q000378:metabolism; D007377:Interleukin-3 / Q000494:pharmacology*; D015240:Phorbol 12,13-Dibutyrate; D010703:Phorbol Esters / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D011955:Receptors, Drug; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D029742:Caenorhabditis elegans Proteins; D002273:Carcinogens; D002352:Carrier Proteins; D007377:Interleukin-3; D010703:Phorbol Esters; D010716:Phosphatidylinositols; D011955:Receptors, Drug; C083141:phorbol ester binding protein; C027776:phorbol ester receptor; D015240:Phorbol 12,13-Dibutyrate; D007294:Inositol; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium