Guanine nucleotide depletion inhibits pre-ribosomal RNA synthesis and causes nucleolar disruption.

Guanine nucleotide depletion inhibits pre-ribosomal RNA synthesis and causes nucleolar disruption. Research Abstract Details 

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Guanine nucleotide depletion inhibits pre-ribosomal RNA synthesis and causes nucleolar disruption. Abstract Text:

Min Huang,Yanshan Ji,Koji Itahana,Yanping Zhang,Beverly Mitchell,Min Huang,Yanshan Ji,Koji Itahana,Yanping Zhang,Beverly Mitchell,

Inosine monophosphate dehydrogenase (IMPDH) is a pivotal enzyme in the de novo pathway of guanine nucleotide biosynthesis. Inhibitors of this enzyme decrease intracellular guanine nucleotide levels by 50-80% and have potential as anti-neoplastic agents. Both mycophenolic acid (MPA) and AVN-944 are highly specific inhibitors of IMPDH that cause cell cycle arrest or apoptosis in lymphocytes and leukemic cell lines. We have examined the mechanisms by which these two agents cause cytotoxicity. Both MPA and AVN-944 inhibit the growth of K562 cells, and induce apoptosis in Raji B and CCRF-CEM T cells. Both compounds strikingly inhibit RNA synthesis within 2h of exposure. Depletion of guanine nucleotides by MPA and AVN-944 also causes an early and near-complete reduction in levels of the 45S precursor rRNA synthesis and the concomitant translocation of nucleolar proteins including nucleolin, nucleophosmin, and nucleostemin from the nucleolus to the nucleoplasm. This efflux correlates temporally with the sustained induction of p53 in cell lines with wild-type p53. We conclude that inhibition of IMPDH causes a primary reduction in rRNA synthesis and secondary nucleolar disruption and efflux of nucleolar proteins that most likely mediate cell cycle arrest or apoptosis. The ability of AVN-944 to induce apoptosis in a number of leukemic cell lines supports its potential utility in the treatment of hematologic malignancies.

Guanine nucleotide depletion inhibits pre-ribosomal RNA synthesis and causes nucleolar disruption. Publishing Authors By Initials

M Huang,Y Ji,K Itahana,Y Zhang,B Mitchell,M Huang,Y Ji,K Itahana,Y Zhang,B Mitchell,

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Guanine nucleotide depletion inhibits pre-ribosomal RNA synthesis and causes nucleolar disruption. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Leukemia research

VOLUME: 32

Page Numbers: 131-41

Journal Abbreviation: Leuk. Res.

ISSN: 0145-2126

DAY: 25

MONTH: 04

YEAR: 2007

Guanine nucleotide depletion inhibits pre-ribosomal RNA synthesis and causes nucleolar disruption. Information

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LANGUAGE: eng

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Grant and Affiliation Information for Guanine nucleotide depletion inhibits pre-ribosomal RNA synthesis and causes nucleolar disruption.

AFFILIATION: Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305-5796, USA.

Country: England

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MEDLINETA: Leuk Res

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