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To: Miljenko Zuanic who wrote (547)	3/26/1999 1:24:00 AM
From: scaram(o)uche	Respond to of 4974

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.

To: Miljenko Zuanic who wrote (547)	3/26/1999 1:45:00 AM
From: scaram(o)uche	Read Replies (1) \| Respond to of 4974

03/25/99 VRTX, 3-D structure of ribavirin bound to IMPDH 03/10/99 MLNM, clones mahogany, obesity target or lab curiosity? 03/09/99 VRTX, initiates phase I trial with p38 MAP kinase inhibitor 03/08/99 CNTO, sales force leverage, LMW heparin with PNU 03/04/99 AGPH, describes crystal structure for VEGFR2 kinase 03/02/99 INCY, using new chemistry from Amersham Pharmacia, flying 03/01/99 GLIA, finishes single-dose portion of phase I, GT-2331 03/01/99 GILD, NXTR merger 02/26/99 MEDI/Ixsys, MAb alliance, including anti-alpha-v beta-3 02/25/99 ONXX, Bayer select lead compound, ras pathway inhibitor