Relationship between apoptosis and the cell cycle in lymphocytes: roles of protein kinase C, tyrosine phosphorylation, and AP1.
The mechanism of switching between the cell cycle and active cell death (apoptosis) was investigated in cytokine-dependent CTLL cells. These cells proliferate in the presence of interleukin 2 (IL2), but accumulate in early G1 and undergo apoptosis in its absence. In the absence of IL2 the cells also become sensitive to glucocorticoid-induced apoptosis. Using specific inhibitors of protein kinase C and tyrosine kinases we established that two signals are required to fully repress cell death and stimulate G1 progression. One of these signals activates protein kinase C (PKC) which represses cell death and the other activates a tyrosine kinase which confers glucocorticoid resistance and permits cell cycle progression. Thus, phorbol esters can activate PKC and maintain cell viability in the absence of IL2, but the cells cannot proliferate. Moreover, the cells remain sensitive to glucocorticoid-induced apoptosis unless the tyrosine kinase-mediated signal is also given. There is a correlation between the presence of AP1 DNA-binding activity and the repression of the cell death pathway. The c-jun gene is expressed constitutively and both IL2 and phorbol esters induce the expression of c-fos to generate a functional AP1 capable of repressing cell death. However, only interleukin 2 can initiate the tyrosine kinase-mediated modification that confers dexamethasone resistance and permits G1 progression. In the absence of IL2 glucocorticoids stimulate AP1 degradation and induce apoptosis.
Walker
P R
PR
Molecular Cell Biology Group, National Research Council, Ottawa, Canada.
Kwast-Welfeld
J
J
Gourdeau
H
H
Leblanc
J
J
Neugebauer
W
W
Sikorska
M
M
D033961:Adaptor Protein Complex 1; D033965:Adaptor Protein Complex alpha Subunits; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002453:Cell Cycle; D002454:Cell Differentiation; D002460:Cell Line / Q000187:drug effects; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D016762:Genes, fos; D007376:Interleukin-2 / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects*; D014443:Tyrosine / Q000378:metabolism
D033961:Adaptor Protein Complex 1; D033965:Adaptor Protein Complex alpha Subunits; D033942:Adaptor Proteins, Vesicular Transport; D007376:Interleukin-2; D010703:Phorbol Esters; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos; D014443:Tyrosine; D003907:Dexamethasone; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C