Rapamycin inhibition of interleukin-2-dependent p33(cdk2) and p34(cdc2) kinase activation in T lymphocytes

W. G. Morice, G. Wiederrecht, G. J. Brunn, John Siekierka, R. T. Abraham

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Abstract

The immunosuppressant rapamycin (RAP) is a potent inhibitor of the entry of interleukin (IL)-2-stimulated T cells into S-phase. Earlier results indicated that RAP treatment arrested the growth of the murine IL-2-dependent T cell line CTLL-2 in late G1-phase. To explore further the interactions of RAP with the cell cycle control machinery in T cells, we examined the effects of RAP treatment on the activation of the cyclin-dependent kinases p34(cdc2) and p33(cdk2) in G1-phase CTLL-2 cells. Stimulation of factor-deprived cells with IL-2 led to the assembly of high molecular weight complexes containing active p34(cdc2) and p33(cdk2). The appearance of these complexes was explained, at least in part, by the association of both cyclin-dependent kinases with IL-2-induced cyclin A. RAP treatment profoundly inhibited both cyclin A expression and the appearance of active cyclin A-cyclin-dependent kinase complexes in IL-2-stimulated, late G1-phase CTLL-2 cells. Although p34(cdc2) activation was largely dependent on association with cyclin A, a significant proportion of the active p33(cdk2) pool was complexed with cyclin E. In contrast to cyclin A, the IL-2-induced accumulation of cyclin E in G1- phase cells was only partially suppressed by RAP, and cyclin E-p33(cdk2) complexes were readily detected in drug-treated cells. These cyclin E- cyclin-dependent kinase complexes were nonetheless devoid of histone H1 kinase activity. The inhibitory effects of RAP on the activation of cyclin E- and cyclin A-associated cyclin-dependent kinases suggest that one or both events participate in the regulation of T cell entry into S-phase.

Original languageEnglish
Pages (from-to)22737-22745
Number of pages9
JournalJournal of Biological Chemistry
Volume268
Issue number30
StatePublished - 1 Jan 1993

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T-cells
Cyclin A
Sirolimus
Cyclin E
Interleukin-2
Cyclin-Dependent Kinases
Phosphotransferases
Chemical activation
T-Lymphocytes
G1 Phase
S Phase
Cells
Association reactions
Immunosuppressive Agents
Cell Cycle Checkpoints
Machinery
Molecular Weight
Molecular weight
Cell Line
Growth

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Morice, W. G. ; Wiederrecht, G. ; Brunn, G. J. ; Siekierka, John ; Abraham, R. T. / Rapamycin inhibition of interleukin-2-dependent p33(cdk2) and p34(cdc2) kinase activation in T lymphocytes. In: Journal of Biological Chemistry. 1993 ; Vol. 268, No. 30. pp. 22737-22745.
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title = "Rapamycin inhibition of interleukin-2-dependent p33(cdk2) and p34(cdc2) kinase activation in T lymphocytes",
abstract = "The immunosuppressant rapamycin (RAP) is a potent inhibitor of the entry of interleukin (IL)-2-stimulated T cells into S-phase. Earlier results indicated that RAP treatment arrested the growth of the murine IL-2-dependent T cell line CTLL-2 in late G1-phase. To explore further the interactions of RAP with the cell cycle control machinery in T cells, we examined the effects of RAP treatment on the activation of the cyclin-dependent kinases p34(cdc2) and p33(cdk2) in G1-phase CTLL-2 cells. Stimulation of factor-deprived cells with IL-2 led to the assembly of high molecular weight complexes containing active p34(cdc2) and p33(cdk2). The appearance of these complexes was explained, at least in part, by the association of both cyclin-dependent kinases with IL-2-induced cyclin A. RAP treatment profoundly inhibited both cyclin A expression and the appearance of active cyclin A-cyclin-dependent kinase complexes in IL-2-stimulated, late G1-phase CTLL-2 cells. Although p34(cdc2) activation was largely dependent on association with cyclin A, a significant proportion of the active p33(cdk2) pool was complexed with cyclin E. In contrast to cyclin A, the IL-2-induced accumulation of cyclin E in G1- phase cells was only partially suppressed by RAP, and cyclin E-p33(cdk2) complexes were readily detected in drug-treated cells. These cyclin E- cyclin-dependent kinase complexes were nonetheless devoid of histone H1 kinase activity. The inhibitory effects of RAP on the activation of cyclin E- and cyclin A-associated cyclin-dependent kinases suggest that one or both events participate in the regulation of T cell entry into S-phase.",
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Rapamycin inhibition of interleukin-2-dependent p33(cdk2) and p34(cdc2) kinase activation in T lymphocytes. / Morice, W. G.; Wiederrecht, G.; Brunn, G. J.; Siekierka, John; Abraham, R. T.

In: Journal of Biological Chemistry, Vol. 268, No. 30, 01.01.1993, p. 22737-22745.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Rapamycin inhibition of interleukin-2-dependent p33(cdk2) and p34(cdc2) kinase activation in T lymphocytes

AU - Morice, W. G.

AU - Wiederrecht, G.

AU - Brunn, G. J.

AU - Siekierka, John

AU - Abraham, R. T.

PY - 1993/1/1

Y1 - 1993/1/1

N2 - The immunosuppressant rapamycin (RAP) is a potent inhibitor of the entry of interleukin (IL)-2-stimulated T cells into S-phase. Earlier results indicated that RAP treatment arrested the growth of the murine IL-2-dependent T cell line CTLL-2 in late G1-phase. To explore further the interactions of RAP with the cell cycle control machinery in T cells, we examined the effects of RAP treatment on the activation of the cyclin-dependent kinases p34(cdc2) and p33(cdk2) in G1-phase CTLL-2 cells. Stimulation of factor-deprived cells with IL-2 led to the assembly of high molecular weight complexes containing active p34(cdc2) and p33(cdk2). The appearance of these complexes was explained, at least in part, by the association of both cyclin-dependent kinases with IL-2-induced cyclin A. RAP treatment profoundly inhibited both cyclin A expression and the appearance of active cyclin A-cyclin-dependent kinase complexes in IL-2-stimulated, late G1-phase CTLL-2 cells. Although p34(cdc2) activation was largely dependent on association with cyclin A, a significant proportion of the active p33(cdk2) pool was complexed with cyclin E. In contrast to cyclin A, the IL-2-induced accumulation of cyclin E in G1- phase cells was only partially suppressed by RAP, and cyclin E-p33(cdk2) complexes were readily detected in drug-treated cells. These cyclin E- cyclin-dependent kinase complexes were nonetheless devoid of histone H1 kinase activity. The inhibitory effects of RAP on the activation of cyclin E- and cyclin A-associated cyclin-dependent kinases suggest that one or both events participate in the regulation of T cell entry into S-phase.

AB - The immunosuppressant rapamycin (RAP) is a potent inhibitor of the entry of interleukin (IL)-2-stimulated T cells into S-phase. Earlier results indicated that RAP treatment arrested the growth of the murine IL-2-dependent T cell line CTLL-2 in late G1-phase. To explore further the interactions of RAP with the cell cycle control machinery in T cells, we examined the effects of RAP treatment on the activation of the cyclin-dependent kinases p34(cdc2) and p33(cdk2) in G1-phase CTLL-2 cells. Stimulation of factor-deprived cells with IL-2 led to the assembly of high molecular weight complexes containing active p34(cdc2) and p33(cdk2). The appearance of these complexes was explained, at least in part, by the association of both cyclin-dependent kinases with IL-2-induced cyclin A. RAP treatment profoundly inhibited both cyclin A expression and the appearance of active cyclin A-cyclin-dependent kinase complexes in IL-2-stimulated, late G1-phase CTLL-2 cells. Although p34(cdc2) activation was largely dependent on association with cyclin A, a significant proportion of the active p33(cdk2) pool was complexed with cyclin E. In contrast to cyclin A, the IL-2-induced accumulation of cyclin E in G1- phase cells was only partially suppressed by RAP, and cyclin E-p33(cdk2) complexes were readily detected in drug-treated cells. These cyclin E- cyclin-dependent kinase complexes were nonetheless devoid of histone H1 kinase activity. The inhibitory effects of RAP on the activation of cyclin E- and cyclin A-associated cyclin-dependent kinases suggest that one or both events participate in the regulation of T cell entry into S-phase.

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M3 - Article

VL - 268

SP - 22737

EP - 22745

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

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ER -