Document Detail

Genetic analysis of adenovirus E1A: induction of genetic instability and altered cell morphologic and growth characteristics are segregatable functions.
MedLine Citation:
PMID:  9748479     Owner:  NLM     Status:  MEDLINE    
Single multifunctional oncoproteins contribute to genomic instability development, but relationships between one or more oncoprotein-associated activities and genetic changes accompanying tumor cell progression are uncertain. Using NIH 3T3 derivative EN/NIH 2-20 containing transcriptionally silent neomycin phosphotransferase gene (neo) integrants with undetectable spontaneous reactivations, we studied wild-type (WT) and mutant adenovirus E1A-induced neo reactivation by neo-allelic rearrangement. WT E1A expression, yielding differential splice transcripts 12S and 13S and resulting in altered cell morphologic and growth characteristics, produced neo reactivations in 9 of 21 subclones (median rate per cell, 35 x 10(-6); range, 0.33 x 10(-6) to 936 x 10(-6)). Only 3 of 17 cell lines expressing CTdl976, a '12S' functional equivalent inducing altered cell morphologic and growth characteristics while lacking the 13S trans activation domain, yielded neo reactivations (range, 0.33 x 10(-6) to 0.67 x 10(-6)). One of 21 subclones expressing NTdl646, an E1A mutant retaining the trans domain but lacking p300 binding activity and the ability to alter cell morphologic and growth characteristics, produced neo reactivations (8.7 x 10(-6)). Other E1A mutants, all lacking the ability to alter cell morphologic and growth characteristics while binding pRb but variously lacking the trans domain and binding for p107 and/or p300, displayed undetectable neo-reactivations. 98 EN/NIH 2-20 derivatives coexpressing complementary mutant E1As exhibited altered morphologic and growth features, but only 10 of these produced neo reactivations, and maximum rates (14 x 10(-6)) were substantially lower than those in comparably derived, morphologically altered E1AWT-expressing counterparts (497 x 10(-6)). These findings suggest that maximum rates of gene reactivations by genomic rearrangement require the collective activities of functional domains assembled in single multifunctional proteins (or complexes) while altered cell morphologic and growth characteristics may arise through comparable sets of functional domains distributed across more than one protein (or complex).
R Drews; M Kolker; C Moran; D Sachar; V Chan; L Schnipper
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Mutation research     Volume:  421     ISSN:  0027-5107     ISO Abbreviation:  Mutat. Res.     Publication Date:  1998 Oct 
Date Detail:
Created Date:  1998-10-20     Completed Date:  1998-10-20     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0400763     Medline TA:  Mutat Res     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  9-25     Citation Subset:  IM    
Copyright Information:
Copyright 1998 Elsevier Science B.V.
Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory of Beth Israel Deaconess Medical Center, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
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MeSH Terms
3T3 Cells
Adenoviridae / genetics*
Adenovirus E1A Proteins / genetics*,  physiology
Anti-Bacterial Agents / pharmacology
Cell Division
Cell Size
Gene Expression
Gene Rearrangement / physiology*
Genetic Complementation Test
Gentamicins / pharmacology
Kanamycin Kinase / genetics*
RNA Splicing
RNA, Messenger / analysis
Sequence Deletion
Transcriptional Activation / genetics
Grant Support
AG-00294-09/AG/NIA NIH HHS
Reg. No./Substance:
0/Adenovirus E1A Proteins; 0/Anti-Bacterial Agents; 0/Gentamicins; 0/RNA, Messenger; 49863-47-0/antibiotic G 418; EC Kinase

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