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Mol. Cell. Biol. 22 (18): 6611-6626

Copyright © 2002 by the American Society for Microbiology. All rights reserved.

Microtubule-Dependent Subcellular Redistribution of the Transcriptional Coactivator p/CIP

Majdi S. Qutob,1,2,3 Rabindra N. Bhattacharjee,1,2,4 Elisa Pollari,1,2,4 Siu Pok Yee,1,2,3 and Joseph Torchia1,2,4*

Cancer Research Laboratories, London Regional Cancer Centre,1 Departments of Oncology,2 Biochemistryand,3 Pharmacology and Toxicology, The University of Western Ontario, London, Ontario, Canada4

Received for publication 27 November 2001. Revision received 15 January 2002. Accepted for publication 6 June 2002.

Abstract: The transcriptional coactivator p/CIP is a member of a family of nuclear receptor coactivator/steroid receptor coactivator (NCoA/SRC) proteins that mediate the transcriptional activities of nuclear hormone receptors. We have found that p/CIP is predominantly cytoplasmic in a large proportion of cells in various tissues of the developing mouse and in a number of established cell lines. In mouse embryonic fibroblasts, serum deprivation results in the redistribution of p/CIP to the cytoplasmic compartment and stimulation with growth factors or tumor-promoting phorbol esters promotes p/CIP shuttling into the nucleus. Cytoplasmic accumulation of p/CIP is also cell cycle dependent, occurring predominantly during the S and late M phases. Leptomycin B (LMB) treatment results in a marked nuclear accumulation, suggesting that p/CIP undergoes dynamic nuclear export as well as import. We have identified a strong nuclear import signal in the N terminus of p/CIP and two leucine-rich motifs in the C terminus that resemble CRM-1-dependent nuclear export sequences. When fused to green fluorescent protein, the nuclear export sequence region is cytoplasmic and is retained in the nucleus in an LMB-dependent manner. Disruption of the leucine-rich motifs prevents cytoplasmic accumulation. Furthermore, we demonstrate that cytoplasmic p/CIP associates with tubulin and that an intact microtubule network is required for intracellular shuttling of p/CIP. Immunoaffinity purification of p/CIP from nuclear and cytosolic extracts revealed that only nuclear p/CIP complexes possess histone acetyltransferase activity. Collectively, these results suggest that cellular compartmentalization of NCoA/SRC proteins could potentially regulate nuclear hormone receptor-mediated events as well as integrating signals in response to different environmental cues.


* Corresponding author. Mailing address: Cancer Research Laboratories, London Regional Cancer Center, London, Ontario, Canada, N6A 4L6. Phone: (519) 685-8692. Fax: (519) 685-8673. E-mail: jtorchia{at}uwo.ca.



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