Document Detail


Microtubule-dependent nuclear-cytoplasmic shuttling of Runx2.
MedLine Citation:
PMID:  16110492     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RUNX/AML transcription factors are critical regulators of cell growth and differentiation in multiple lineages and have been linked to human cancers including acute myelogenous leukemia (RUNX1), as well as breast (RUNX2) and gastric cancers (RUNX3). RUNX proteins are targeted to gene regulatory micro-environments within the nucleus via a specific subnuclear targeting signal. However, the dynamics of RUNX distribution and compartmentalization between the cytoplasm and nucleus is minimally understood. Here we show by immunofluorescence microscopy that RUNX2 relocates from the nucleus to the cytoplasm when microtubules are stabilized by the chemotherapeutic agent taxol. The taxol-dependent cytoplasmic accumulation of RUNX2 is inhibited by leptomycin B, which blocks CRM-1 dependent nuclear export, and is not affected by the protein synthesis inhibitor cycloheximide. Using biochemical assays, we show that endogenous RUNX2 associates with stabilized microtubules in a concentration-dependent manner and that the RUNX2 amino terminus mediates the microtubule association. In soluble fractions of cells, RUNX2 co-immunoprecipitates alpha tubulin suggesting that microtubule binding involves the alpha/beta tubulin subunits. We conclude that RUNX2 associates with microtubules and shuttles between the nucleus and the cytoplasm. We propose that nuclear-cytoplasmic shuttling of RUNX2 may modulate its transcriptional activity, as well as its ability to interface with signal transduction pathways that are integrated at RUNX2 containing subnuclear sites. It is possible that taxol-induced acute depletion of the nuclear levels of RUNX2 and/or other cell growth regulatory factors may represent an alternative pathway by which taxol exerts its biological effects during cancer chemotherapies.
Authors:
Shirwin M Pockwinse; Arun Rajgopal; Daniel W Young; Khwaja A Mujeeb; Jeffrey Nickerson; Amjad Javed; Sambra Redick; Jane B Lian; Andre J van Wijnen; Janet L Stein; Gary S Stein; Stephen J Doxsey
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of cellular physiology     Volume:  206     ISSN:  0021-9541     ISO Abbreviation:  J. Cell. Physiol.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2005-12-05     Completed Date:  2006-03-10     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0050222     Medline TA:  J Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  354-62     Citation Subset:  IM    
Copyright Information:
Copyright (c) 2005 Wiley-Liss, Inc.
Affiliation:
Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
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MeSH Terms
Descriptor/Qualifier:
Active Transport, Cell Nucleus
Cell Line, Tumor
Cell Nucleus / metabolism*
Core Binding Factor Alpha 1 Subunit / metabolism*,  physiology
Cytoplasm / metabolism*
Dimethyl Sulfoxide / pharmacology
Humans
Microtubules / drug effects,  metabolism*,  physiology
Paclitaxel / pharmacology
Tubulin / metabolism*
Grant Support
ID/Acronym/Agency:
P01 CA82834/CA/NCI NIH HHS; P30 DK32520/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Core Binding Factor Alpha 1 Subunit; 0/Tubulin; 33069-62-4/Paclitaxel; 67-68-5/Dimethyl Sulfoxide

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


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