Document Detail


Ornithine decarboxylase over-expression stimulates mitogen-activated protein kinase and anchorage-independent growth of human breast epithelial cells.
MedLine Citation:
PMID:  9009157     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In these experiments we tested the hypothesis that constitutive activation of polyamine(PA) biosynthesis may contribute to mammary carcinogenesis. Spontaneously immortalized normal human MCF-10A breast epithelial cells were infected with the retroviral vector pLOSN containing a cDNA which codes for a truncated and more stable ornithine decarboxylase (ODC), the rate-limiting enzyme in PA synthesis. Upon chronic selective pressure with alpha-difluoromethyl-ornithine (DFMO) (an irreversible inhibitor of ODC), infected MCF-10A cells exhibited an approximately 250-fold increase in ODC activity, which persisted despite discontinuation of DFMO. ODC-over-expressing MCF-10A cells showed a modest decrease in S-adenosylmethionine decarboxylase and an increase in spermidine/spermineN1-acetyltransferase. Analysis of cellular PA profile revealed a selective accumulation of putrescine without alterations in spermidine and spermine contents. Lesser degrees of increased ODC activity were obtained reproducibly by re-exposing the cells to incremental small doses of DFMO. We observed a bell-shaped dose-related positive effect of ODC activity on clonogenicity in soft agar of MCF-10A cells. Since anchorage-dependent growth was actually reduced, such positive influence on this feature of transformation was not a non-specific consequence of a growth advantage provided by ODC over-expression. In addition, we observed a close parallelism between the dose-dependent effects of ODC expression on clonogenicity and activity of the ERK-2 kinase, a central element of the MAPK cascade. Our data demonstrate an interaction between PA and the MAPK signalling pathway and suggest that the latter may be involved in ODC-induced transformation of mammary epithelial cells.
Authors:
A Manni; R Wechter; S Gilmour; M F Verderame; D Mauger; L M Demers
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  70     ISSN:  0020-7136     ISO Abbreviation:  Int. J. Cancer     Publication Date:  1997 Jan 
Date Detail:
Created Date:  1997-02-20     Completed Date:  1997-02-20     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  175-82     Citation Subset:  IM    
Affiliation:
Department of Medicine, Milton S. Hershey Medical School, Pennsylvania State University, Hershey, USA.
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MeSH Terms
Descriptor/Qualifier:
Acetyltransferases / metabolism
Adenosylmethionine Decarboxylase / metabolism
Breast / cytology*,  drug effects,  enzymology
Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
Cell Line, Transformed
Cell Transformation, Neoplastic / genetics*
Colony-Forming Units Assay
DNA, Complementary / genetics
Eflornithine / pharmacology
Enzyme Induction
Epithelial Cells
Epithelium / drug effects,  enzymology
Female
Genes, ras
Humans
Mitogen-Activated Protein Kinase 1
Ornithine Decarboxylase / antagonists & inhibitors,  biosynthesis,  chemistry,  genetics,  physiology*
Polyamines / metabolism
Recombinant Fusion Proteins / metabolism
Signal Transduction / physiology
Transfection
Grant Support
ID/Acronym/Agency:
CA40011-11/CA/NCI NIH HHS; R-29CA55066/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Complementary; 0/Polyamines; 0/Recombinant Fusion Proteins; 70052-12-9/Eflornithine; EC 2.3.1.-/Acetyltransferases; EC 2.3.1.57/diamine N-acetyltransferase; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 4.1.1.17/Ornithine Decarboxylase; EC 4.1.1.50/Adenosylmethionine Decarboxylase

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


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