Identification of multiple cell cycle regulatory functions of p57 Kip2 in human T lymphocytes

Guiming Li, Joanne Domenico, Joseph J. Lucas, Erwin W. Gelfand

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

The specific functions of p57Kip2 in lymphocytes have not yet been fully elucidated. In this study, it is shown that p57Kip2, which is a member of the Cip/Kip family of cyclin-dependent kinase inhibitors, is present in the nuclei of normal resting (G0) T cells from peripheral blood and in the nuclei of the T cell-derived Jurkat cell line. Activation through the TCR results in rapid transport of cytoplasmic cyclin-dependent kinase 6 (cdk6) to nuclei, where it associates with cyclin D and p57 KiP2 in active enzyme complexes. Using purified recombinant proteins, it was shown in vitro that addition of p57Kip2 protein to a mixture of cyclin D2 and cdk6 enhanced the association of the latter two proteins and resulted in phosphorylation of p57Kip2. To probe further the function of p57KiP2, Jurkat cells stably transfected with a plasmid encoding p57Kip2 under control of an inducible (tetracycline) promoter were made. Induction of p57Kip2 resulted in increased association of cdk6 with cyclin D3, without receptor-mediated T cell stimulation. The overall amounts of cdk6 and cyclin D3, and also of cdk4 and cyclin E, remained unchanged. Most notably, increased p57Kip2 levels resulted in marked inhibition of both cyclin E- and cyclin A-associated cdk2 kinase activities and a decrease in cyclin A amounts. Therefore, although facilitating activation of cdk6, the ultimate outcome of p57Kip2 induction was a decrease in DNA synthesis and cell proliferation. The results indicate that p57Kip2 is involved in the regulation of several aspects of the T cell cycle.

Original languageEnglish (US)
Pages (from-to)2383-2391
Number of pages9
JournalJournal of Immunology
Volume173
Issue number4
DOIs
StatePublished - Aug 15 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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