Blood 1998 Apr 15;91(8):2896-904
Effects of guanine nucleotide depletion on cell cycle progression in human T
lymphocytes.
Laliberte J, Yee A, Xiong Y, Mitchell BS
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, USA.
Depletion of guanine nucleotide pools after inhibition of inosine monophosphate dehydrogenase (IMPDH) potently inhibits DNA
synthesis by arresting cells in G1 and has been shown to induce the differentiation of cultured myeloid and erythroid cell lines, as
well as chronic granulocytic leukemic cells after blast transformation. Inhibitors of IMPDH are also highly effective as
immunosuppressive agents. The mechanism underlying these pleiotropic effects of depletion of guanine nucleotides is unknown.
We have examined the effects of mycophenolic acid (MPA), a potent IMPDH inhibitor, on the cell cycle progression of activated
normal human T lymphocytes. MPA treatment resulted in the inhibition of pRb phosphorylation and cell entry into S phase. The
expression of cyclin D3, a major component of the cyclin-dependent kinase (CDK) activity required for pRb phosphorylation, was
completely abrogated by MPA treatment of T cells activated by interleukin-2 (IL-2) and leucoagglutinin (PHA-L), whereas the
expression of cyclin D2, CDK6, and CDK4 was more mildly attenuated. The direct kinase activity of a complex
immunoprecipitated with anti-CDK6 antibody was also inhibited. In addition, MPA prevented the IL-2-induced elimination of
p27(Kip1), a CDK inhibitor, and resulted in the retention of high levels of p27(Kip1) in IL-2/PHA-L-treated T cells bound to
CDK2. These results indicate that inhibition of the de novo synthesis of guanine nucleotides blocks the transition of normal
peripheral blood T lymphocytes from G0 to S phase in early- to mid-G1 and that this cell cycle arrest results from inhibition of the
induction of cyclin D/CDK6 kinase and the elimination of p27(Kip1) inhibitory activity. |
