Protein kinase A regulates expression of p27(kip1) and cyclin D3 to suppress proliferation of leukemic T cell lines.
J Biol Chem
; 276(36): 33854-60, 2001 Sep 07.
Article
de En
| MEDLINE
| ID: mdl-11457838
ABSTRACT
Peripheral homeostasis and tolerance requires the suppression or removal of excessive or harmful T lymphocytes. This can occur either by apoptosis through active antigen-induced death or cytokine withdrawal. Alternatively, T cell activation can be suppressed by agents that activate the cAMP-dependent protein kinase (PKA) signaling pathway, such as prostaglandin E2. Stimulation of PKA inhibits lymphocyte proliferation and immune effector functions. Here we have investigated the mechanism by which activation of PKA induces inhibition of proliferation in human leukemic T cell lines. Using a variety of agents that stimulate PKA, we can arrest Jurkat and H9 leukemic T cells in the G(1) phase of the cell cycle, whereas cell viability is hardly affected. This G(1) arrest is associated with an inhibition of cyclin D/Cdk and cyclin E/Cdk kinase activity. Interestingly, expression of cyclin D3 is rapidly reduced by PKA activation, whereas expression of the Cdk inhibitor p27(kip1) is induced. Ectopic expression of cyclin D3 can override the growth suppression induced by PKA activation to some extent, indicating that growth inhibition of leukemic T cells by PKA activation is partially dependent on down-regulation of cyclin D3 expression. Taken together our data suggest that immunosuppression by protein kinase A involves regulation of both cyclin D3 and p27(kip1) expression.
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Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Leucémies
/
Cyclines
/
Cyclic AMP-Dependent Protein Kinases
/
Protéines du cycle cellulaire
/
Protéines suppresseurs de tumeurs
Limites:
Humans
Langue:
En
Journal:
J Biol Chem
Année:
2001
Type de document:
Article
Pays d'affiliation:
Pays-Bas