Regulation of synthesis and activity of the PLSTIRE protein (cyclin- dependent kinase 6 (cdk6)), a major cyclin D-associated cdk4 homologue in normal human T lymphocytes

Joseph J. Lucas, Agota Szepesi, Jaime F. Modiano, Joanne Domenico, Erwin W. Gelfand

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52 Scopus citations

Abstract

The PLSTIRE protein (cyclin-dependent kinase 6 (cdk6)), which shares extensive sequence homology (~70%) with cdk4, was identified as the earliest inducible member of the cdk family of proteins in human T lymphocytes induced to proliferate in vitro by stimulation either with phorbol 12,13-dibutyrate and ionomycin (PDB/I) or PHA. The p40(cdk6) protein was present in resting cells and increased amounts were detected 6 h after stimulation. It increased in amount throughout the first cell cycle but was present in reduced amounts at later times. Activity of the kinase, determined by in vitro phosphorylation of recombinant truncated retinoblastoma tumor suppressor gene (Rb) protein (p60(Rb)), paralleled p40(cdk6) protein amounts. Cyclins D2 and D3 were the major cyclins associated with p40(cdk6), with D2 predominating in early G1 phase. Both PDB and ionomycin were required for maximal accumulation of p40(cdk6), but either agent alone stimulated some increase in amount and activity of the protein. p40(cdk6) also increased in amount in cells activated in the presence of cyclosporin A or FK506, drugs that inhibit production of IL-2 and cell proliferation, suggesting that initial induction occurred independently of IL-2-mediated cell cycle progression. Furthermore, increased accumulation of p40(cdk6) protein and activity occurred in cells rendered 'competent' (responsive to IL-2) by a brief treatment with PDB/I. Thus, increased accumulation of the protein and its activity begin before IL- 2/IL-2 receptor interaction, suggesting that the cdk6-cyclin D2 complex might be involved in acquisition of the competent state in human T lymphocytes.

Original languageEnglish (US)
Pages (from-to)6275-6284
Number of pages10
JournalJournal of Immunology
Volume154
Issue number12
StatePublished - 1995

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