Hsp90-binding Immunophilins Link p53 to Dynein During p53 Transport to the Nucleus

Galigniana, Mario D.; Harrell, Jennifer M.; O'Hagen, Heather M.; Ljungman, Mats; Pratt, William B.

doi:10.1074/jbc.m402223200

Cited by 146 publications

(124 citation statements)

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“…Moreover, all of these proteins were found to be physically associated as part of a complex containing at least the immunophilin FKBP52 and the microtubule-binding protein dynein (Figure 8a). This is in agreement with the previously described interaction among FKBP52, Hsp90 and dynein, a complex where the immunophilin acts as an anchor or adaptor that links the cargo protein complex to be transported by the microtubule machinery via dynein motor proteins (Galigniana et al, 2004).…”

Section: Resultssupporting

confidence: 92%

“…Although there is not much evidence concerning the mechanism of AIF subcellular trafficking, and the specific mechanism by which RAC3 inhibits the AIF nuclear localization is not clear, in this study, we demonstrate that both molecules translocate to the nucleus after H 2 O 2 stimulation as part of a protein complex containing Hsp90 and the immunophilin FKBP52, which are in turn associated with the microtubuletrafficking machinery (Pratt and Toft, 2003;Galigniana et al, 2004). In view of these observations, we may speculate that high levels of RAC3 may interfere with the structure of the protein complex, perhaps by downtitration or squelching of some components that are required for nuclear translocation, as well as with the recruitment of molecules that cooperates with a cytosolic retention.…”

Section: Discussionmentioning

confidence: 60%

“…In addition, it is well known that Hsp70 is usually associated with Hsp90, which is involved in the regulation of signaling protein function and trafficking together with immunophilins and the microtubule-associated motor protein dynein (Pratt and Toft, 2003;Galigniana et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

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The p160 nuclear receptor co-activator RAC3 exerts an anti-apoptotic role through a cytoplasmatic action

et al. 2007

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The p160 nuclear receptor co-activators represent a family of molecules, which are recruited by steroid nuclear receptors as well as other transcription factors that are overexpressed in several tumors. We investigated the role of one member of this family on the sensitivity of cells to apoptosis. We observed that overexpression of the RAC3 (receptor-associated co-activator-3) p160 co-activator inhibits hydrogen peroxide-induced cell death in human embryonic kidney 293 (HEK293) cells. The mechanism involves the activation of anti-apoptotic pathways mediated through enhanced nuclear factor kappa B (NFjB) activity, inhibition of caspase-9 activation, diminished apoptotic-inducing factor (AIF) nuclear localization and a change in the activation pattern of several kinases, including an increase in both AKT and p38 kinase activities, and inhibition of ERK2. Moreover, RAC3 has been found associated with a protein complex containing AIF, Hsp90 and dynein, suggesting a role for the coactivator in the cytoplasmatic nuclear transport of these proteins associated with cytoskeleton. These results demonstrate that there are several molecular pathways that could be affected by their overexpression, including those not restricted to steroid regulation or the nuclear action of co-activators, which results in diminished sensitivity to apoptosis. Furthermore, this could represent one mechanism by which co-activators contribute to tumor development.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 60%

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The p160 nuclear receptor co-activator RAC3 exerts an anti-apoptotic role through a cytoplasmatic action

et al. 2007

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“…Heterocomplexes containing the GR and the hsp90 chaperone interact with the dynein intermediate chain (39). There is also recent functional evidence that dynein mediates the trafficking of MT-bound p53 toward the nucleus upon activation (4) and that hsp90-binding immunophilins link p53 to dynein during this transport (54). More surprisingly, interactions may also take place that involve kinesins as the MLK2 kinase (5) or the tumor suppressor APC were shown to interact with the kinesin-like KIF3 (55).…”

Section: Figmentioning

confidence: 99%

STAT5B-mediated Growth Hormone Signaling Is Organized by Highly Dynamic Microtubules in Hepatic Cells

Phung-Koskas

Pilon

Poüs

et al. 2005

Journal of Biological Chemistry

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In the last decade, the notion that microtubules are critical to the spatial organization of signal transduction and contribute to the transmission of signals to downstream targets has been proposed. Because the STAT5B transduction and transcription factor is the major STAT protein activated by growth hormone stimulation in hepatocytes and is a crossroads between many signaling pathways, we studied the involvement of microtubules in STAT5B-mediated growth hormone signaling pathway in the highly differentiated and polarized WIF-B hepatic cell line. We showed that depolymerization of the microtubule network impaired STAT5B translocation to the nucleus upon growth hormone treatment. A significant amount of STAT5B binds to microtubules, while STAT5A and STAT3 are exclusively compartmentalized in the cytosol. Moreover, taxol-induced stabilization of microtubules released STAT5B from its binding, and we show that STAT5B binds specifically to the highly dynamic microtubules and is absent of the stable microtubule subpopulation. The specific involvement of dynamic microtubule subpopulation in growth hormone signaling pathway was confirmed by the inhibition of growth hormone-induced STAT5B nuclear translocation after stabilization of microtubules or specific disruption of highly dynamic microtubules. Upon growth hormone treatment, MT-bound STAT5B was rapidly released from microtubules by a dynein-dependent transport to the nucleus. Altogether, our findings indicate that the labile microtubule subpopulation specifically and dynamically organizes STAT5B-mediated growth hormone signaling in hepatic cells.Once bound to specific receptors, a large number of cytokines, growth factors, and hormones act through a sequence of steps allowing the rapid transport of information from the plasma membrane to subcellular targets. This information often results in the phosphorylation of transcription factors that subsequently migrate to the nucleus where they initiate specific gene transcription. How transcription factors are organized as molecular targets downstream of receptor activation and how they move rapidly through the cytoplasm from their activation site to the nucleus often remains unclear. The notion that microtubules (MTs) 1 might be involved in the cytoplasmic activation and/or trafficking of various transcription factors and protein kinases has emerged, as many signal transduction molecules, including transcription factors and protein kinases, have been shown to interact with MTs (1). For example, the glucocorticoid receptor was shown to colocalize with the MT network in mammalian cells (2, 3). The tumor suppressor protein p53 also uses MT tracks to migrate to the nucleus (4). Various protein kinases such as the MAP kinase kinase kinase MLK2 (5) or the MAP kinases ERK1 and ERK2 (6) were also shown to interact or to colocalize with MTs or with microtubule-associated proteins (7).In this study, we investigated the putative involvement of the MT network in GH signaling in the highly differentiated WIF-B hepatic cell line (8, 9...

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“…These drugs rapidly inactivate the refolding machinery and reveal the biological consequences of cellular chaperone function. For example, geldanamycin, an inhibitor of heat shock protein 90 (Hsp90), was used to define this protein's substantial role in p53 regulation (16). Chemical chaperones complement these reagents by enhancing the folding energy of specific targets.…”

mentioning

confidence: 99%

Reclamation of Proteins from the Cellular Scrap Heap

Gestwicki

2006

ACS Chem. Biol.

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Hsp90-binding Immunophilins Link p53 to Dynein During p53 Transport to the Nucleus

Cited by 146 publications

References 50 publications

The p160 nuclear receptor co-activator RAC3 exerts an anti-apoptotic role through a cytoplasmatic action

The p160 nuclear receptor co-activator RAC3 exerts an anti-apoptotic role through a cytoplasmatic action

STAT5B-mediated Growth Hormone Signaling Is Organized by Highly Dynamic Microtubules in Hepatic Cells

Reclamation of Proteins from the Cellular Scrap Heap

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