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Molecular and Cellular Biology, September 2002, p. 6611-6626, Vol. 22, No. 18
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.18.6611-6626.2002
Copyright © 2002, 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 27 November 2001/ Returned for modification 15 January 2002/ Accepted 6 June 2002

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.

Molecular and Cellular Biology, September 2002, p. 6611-6626, Vol. 22, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.18.6611-6626.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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