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1 Department of Physiology and Biophysics and 2 Department of Pharmacology, College of Medicine, University of Tennessee, Memphis, Tennessee 38163
Cell growth and
migration are essential processes for the differentiation, maintenance,
and repair of the intestinal epithelium. Epidermal growth factor (EGF)
is an important factor in the reorganization of the cytoskeleton
required for both processes. Because we had previously found
significant changes in the cytoskeleton during polyamine deficiency, it
was of interest to know whether those changes could prevent EGF from
stimulating growth and migration. Polyamine biosynthesis in IEC-6 cells
was interrupted by treatment with 
-difluoromethylornithine (DFMO), a
specific inhibitor of ornithine decarboxylase, the primary
rate-limiting enzyme of polyamine biosynthesis. DFMO halted cell
proliferation and inhibited cell migration, and neither function could
be normally stimulated by EGF. Immunocytochemistry of the transferrin
receptor (used as a marker for the endocytic pathway) revealed an
abnormal distribution of the EGF receptor (EGFR) 10 min after binding
EGF. Polyamine deficiency depleted the cells of interior
microfilaments, thickened the actin cortex, and prevented the prompt
association of EGF-bound EGFR with actin. EGF-stimulated 170-kDa
protein tyrosine phosphorylation and the kinase activity of purified
membrane EGFR were reduced by 50%. Immunoprecipatated EGFR protein
concentration, however, was not reduced by polyamine deficiency. All of
these changes could be prevented by supplementation with putrescine.
Cytoskeletal disruption, reduced EGFR phosphorylation and kinase
activity, aberrant intracellular EGFR distribution, and delayed
association with actin filaments suggest a partial explanation for the
dependence of epithelial cell growth and migration on polyamines.
transferrin receptor; cell proliferation; cell migration; actin filaments; epidermal growth factor receptor
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