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J. Biol. Chem., Vol. 283, Issue 17, 11823-11831, April 25, 2008

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The Nucleolus Exhibits an Osmotically Regulated Gatekeeping Activity That Controls the Spatial Dynamics and Functions of Nucleolin^*

Ling Yang, Jeff M. Reece, Jaiesoon Cho¹, Carl D. Bortner^¶, and Stephen B. Shears²

From the Inositol Signaling Group and the ^¶Molecular Endocrinology Group, NIEHS, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709 and Reecent Technologies, LLC, Durham, North Carolina 27713

We demonstrate that physiologically relevant perturbations in the osmotic environment rheostatically regulate a gatekeeping function for the nucleolus that controls the spatial dynamics and functions of nucleolin. HeLa cells and U2-OS osteosarcoma cells were osmotically challenged with 100-200 mM sorbitol, and the intranuclear distribution of nucleolin was monitored by confocal microscopy. Nucleolin that normally resides in the innermost fibrillar core of the nucleolus, where it assists rDNA transcription and replication, was expelled within 30 min of sorbitol addition. The nucleolin was transferred into the nucleoplasm, but it distributed there non-uniformly; locally high levels accumulated in 4',6-diamidino-2-phenylindole-negative zones containing euchromatic (transcriptionally active) DNA. Inositol pyrophosphates also responded within 30 min of hyperosmotic stress: levels of bisdiphosphoinositol tetrakisphosphate increased 6-fold, and this was matched by decreased levels of its precursor, diphosphoinositol pentakisphosphate. Such fluctuations in inositol pyrophosphate levels are of considerable interest, because, according to previously published in vitro data, they regulate the degree of phosphorylation of nucleolin through a novel kinase-independent phosphotransferase reaction ( Saiardi, A., Bhandari, A., Resnick, R., Cain, A., Snowman, A. M., and Snyder, S. H. (2004) Science 306, 2101-2105[Abstract/Free Full Text] ). However, by pharmacologically intervening in inositol pyrophosphate metabolism, we found that it did not supervise the osmotically driven switch in the biological activities of nucleolin in vivo.

Received for publication, January 11, 2008 , and in revised form, February 15, 2008.

^* This work was supported by the Intramural Research Program of the NIH/National Institute of Environmental Health Sciences. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Animal Science and Environment, College of Animal Bioscience and Technology, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, South Korea.

² To whom correspondence should be addressed: Tel.: 919-541-0793; Fax: 919-541-0559; E-mail: Shears{at}niehs.nih.gov.

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