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Prepublished online as a Blood First Edition Paper on February 27, 2003; DOI 10.1182/blood-2002-08-2547. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-08-2547v1 101/12/4958    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gu, J. J. Articles by Mitchell, B. S. Search for Related Content PubMed PubMed Citation Articles by Gu, J. J. Articles by Mitchell, B. S. Related Collections Apoptosis Signal Transduction Hematopoiesis and Stem Cells Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 June 2003, Vol. 101, No. 12, pp. 4958-4965 NEOPLASIA Induction of apoptosis in IL-3–dependent hematopoietic cell lines by guanine nucleotide depletion Jing Jin Gu, Karen Gathy, Lalaine Santiago, Eric Chen, Min Huang, Lee M. Graves, and Beverly S. Mitchell From the Lineberger Comprehensive Cancer Center, Departments of Pharmacology and Medicine, University of North Carolina at Chapel Hill. Inosine 5'-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes the conversion of IMP to xanthosine monophosphate (XMP) at the branch point of purine nucleotide biosynthesis, leading to the generation of guanine nucleotides. Inhibition of IMPDH results in the depletion of guanine nucleotides, prevents cell growth by G1 arrest, and induces cell differentiation in a cell-type–specific manner. The molecular and sensing mechanisms underlying these effects are not clear. We have examined the induction of apoptosis by mycophenolic acid (MPA), a specific IMPDH inhibitor, in interleukin-3 (IL-3)–dependent murine hematopoietic cell lines. MPA treatment, at clinically relevant doses, caused apoptosis in 32D myeloid cells and in FL5.12 and BaF3 pre-B cells in the ongoing presence of IL-3. Apoptosis was completely prevented by the addition of guanosine at time points up to 12 hours, after which caspase 3 activity increased and apoptosis was not reversible. MPA treatment caused marked down-regulation of the MAP kinase kinase/extracellular regulatory kinase (MEK/Erk) pathway at 3 hours while simultaneously increasing the phosphorylation of c-Jun kinase. In addition, MPA strongly down-regulated the mammalian target of rapamcyin (mTOR) pathway, as indicated by the decreased phosphorylation of p70 S6 kinase and of 4EBP1. Inhibition of either the mitogen-activated protein kinase (MAPK) or the mTOR pathway alone by standard pharmacologic inhibitors did not induce apoptosis in IL-3–dependent cells, whereas inhibition of both pathways simulated the effects of MPA treatment. These results indicate that IMPDH inhibitors may be effective in modulating signal transduction pathways in hematopoietic cells, suggesting their usefulness in chemotherapeutic regimens for hematologic malignancies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: X.-X. Sun, M.-S. Dai, and H. Lu Mycophenolic Acid Activation of p53 Requires Ribosomal Proteins L5 and L11 J. Biol. Chem., May 2, 2008; 283(18): 12387 - 12392. [Abstract] [Full Text] [PDF] Y. Ji, J. Gu, A. M. Makhov, J. D. Griffith, and B. S. Mitchell Regulation of the Interaction of Inosine Monophosphate Dehydrogenase with Mycophenolic Acid by GTP J. Biol. Chem., January 6, 2006; 281(1): 206 - 212. [Abstract] [Full Text] [PDF] J. J. Gu, L. Santiago, and B. S. Mitchell Synergy between imatinib and mycophenolic acid in inducing apoptosis in cell lines expressing Bcr-Abl Blood, April 15, 2005; 105(8): 3270 - 3277. [Abstract] [Full Text] [PDF]

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