Microtubule-dependent subcellular redistribution of the transcriptional coactivator p/ CIP.
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.[1]References
- Microtubule-dependent subcellular redistribution of the transcriptional coactivator p/CIP. Qutob, M.S., Bhattacharjee, R.N., Pollari, E., Yee, S.P., Torchia, J. Mol. Cell. Biol. (2002) [Pubmed]
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