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Effects of Guanine Nucleotide Depletion on Cell Cycle
Progression in Human T Lymphocytes
Josée Laliberté,
Ann Yee,
Yue Xiong, and
Beverly S. Mitchell
From the Departments of Pharmacology, Biochemistry, and Biophysics,
University of North Carolina at Chapel Hill, Chapel Hill, NC; the
Department of Medicine, University of North Carolina at Chapel Hill,
Chapel Hill, NC; and the Lineberger Comprehensive Cancer Center,
University of North Carolina at Chapel Hill, Chapel Hill, NC.
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
p27Kip1, a CDK inhibitor, and resulted in the retention of
high levels of p27Kip1 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
p27Kip1 inhibitory activity.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2896-2904
© 1998 by The American Society of Hematology.
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