Document Detail


Taxol selectively blocks microtubule dependent NF-kappaB activation by phorbol ester via inhibition of IkappaBalpha phosphorylation and degradation.
MedLine Citation:
PMID:  9927206     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Activation of the NF-kappa-B transcription factors has been shown to be directly influenced by changes in the microtubule cytoskeleton network. To better understand cytoskeletal regulation of NF-kappaB, experiments were performed to determine whether the microtubule (MT) stabilizing agent taxol could modulate NF-kappaB activation in the presence of different NF-kappa-B inducers. Pretreatment of murine NIH3T3 and human 293 cells with 5 microM taxol resulted in complete inhibition of phorbol, 12-myristate, 13-acetate (PMA) mediated NF-kappaB activation, detected as the loss of DNA binding and reduced NF-kappaB dependent reporter gene activity. Furthermore, in COS-7 and NIH3T3 cells, PMA-induced Ikappa-Balpha turnover was dramatically reduced in taxol treated cells, mediated via the inhibition of IkappaBalpha phosphorylation. However, taxol did not prevent TNF-alpha induced Ikappa-Balpha phosphorylation, degradation, or NF-kappaB activation, indicating that TNF-alpha acts through a microtubule-independent pathway. In vitro kinase assays with PMA stimulated cell extracts demonstrated that taxol reduced protein kinase C activity by 30%, thus implicating the loss of PKC activity as a possible regulatory target of taxol-mediated suppression of NF-kappa-B. Since PMA causes modulation of cytoarchitecture through PKC activation, microtubule integrity and cell morphology was analysed by indirect immunofluorescence. Both PMA and nocodazole, a MT depolymerizing agent, caused microtubule depolymerization, whereas TNF-alpha did not alter MT integrity; concomitant taxol treatment blocked both nocodazole and PMA induced depolymerization of MTs, as well as NF-kappaB induction, thus demonstrating a link between microtubule depolymerization and NF-kappaB activation. These observations illustrate a novel biological activity of taxol as a selective inhibitor of NF-kappa-B activity, suggesting a link between the state of microtubule integrity and gene regulation.
Authors:
W Spencer; H Kwon; P Crépieux; N Leclerc; R Lin; J Hiscott
Related Documents :
11954826 - Hyperoxia prolongs tumor necrosis factor-alpha-mediated activation of nf-kappab: role o...
20484576 - The scaffold protein tank/i-traf inhibits nf-kappab activation by recruiting polo-like ...
19047046 - Role of src signal transduction pathways in scatter factor-mediated cellular protection.
14574326 - Constitutive nf-kappab dna-binding activity in aml is frequently mediated by a ras/pi3-...
25471136 - Sevoflurane postconditioning protects rat hearts against ischemia-reperfusion injury vi...
11463786 - The cleavage of akt/protein kinase b by death receptor signaling is an important event ...
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Oncogene     Volume:  18     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  1999 Jan 
Date Detail:
Created Date:  1999-02-16     Completed Date:  1999-02-16     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  495-505     Citation Subset:  IM    
Affiliation:
Lady Davis Institute for Medical Research, Department of Microbiology, McGill University, Montreal, Canada.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
3T3 Cells
Animals
Base Sequence
Biopolymers
COS Cells
Cell Line
DNA Primers
DNA-Binding Proteins / antagonists & inhibitors*,  metabolism
Enzyme Activation
Fluorescent Antibody Technique, Indirect
Humans
Hydrolysis
I-kappa B Proteins*
Mice
Microtubules / drug effects*,  enzymology,  metabolism
NF-kappa B / metabolism*
Paclitaxel / pharmacology*
Phosphorylation
Protein Kinase C / metabolism
Tetradecanoylphorbol Acetate / pharmacology*
Chemical
Reg. No./Substance:
0/Biopolymers; 0/DNA Primers; 0/DNA-Binding Proteins; 0/I-kappa B Proteins; 0/NF-kappa B; 139874-52-5/NF-kappaB inhibitor alpha; 16561-29-8/Tetradecanoylphorbol Acetate; 33069-62-4/Paclitaxel; EC 2.7.11.13/Protein Kinase C

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Adenovirus-mediated high expression of BCL-6 in CV-1 cells induces apoptotic cell death accompanied ...
Next Document:  Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF receptor 3 signalin...