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Analysis of dominant-negative mutations of the Caenorhabditis elegans let-60 ras gene

Han, Min and Sternberg, Paul W. (1991) Analysis of dominant-negative mutations of the Caenorhabditis elegans let-60 ras gene. Genes and Development, 5 (12a). pp. 2188-2198. ISSN 0890-9369. doi:10.1101/gad.5.12a.2188.

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The let-60 gene of Caenorhabditis elegans controls the choice between vulval and hypodermal differentiation in response to an inductive signal from the gonad. let-60 encodes a ras protein that acts downstream of the let-23 receptor tyrosine kinase in a signal transduction pathway. Dominant-negative mutations of let-60 [let-60(dn)] cause a reduction of the gene activity in let-60(dn)/+ heterozygotes and a vulva-less mutant phenotype. We have found that nine let-60(dn) mutations cause replacements of conserved residues. Four are in two novel positions; others are in positions known previously to cause dominant-negative mutations in mammalian cells. The locations of these lesions suggest that they disrupt the ability of the ras protein to bind guanine nucleotides. Four let-60(dn) mutant genes were introduced into wild-type animals in the form of extrachromosomal arrays and were found to generate three dominant phenotypes--lethality, vulva-less, or multivulva--depending on gene dose and alleles. The dominant lethality caused by high-dose transgenic let-60(dn) genes suggests a toxic effect of these mutant genes in early development. The dominant-negative effects of these mutations in heterozygotes are likely to be caused by competition between let-60(dn) and let-60(+) protein for a positive regulator. All let-60(dn) mutations interfere with let-60(+) activity, but some alleles have partial constitutive activity, suggesting that the ability to interact with the activator is separable from the ability to exert a physiological effect (stimulation of vulval differentiation). These dn mutations might be useful for interfering with ras-mediated signal transduction pathways in other multicellular organisms.

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Sternberg, Paul W.0000-0002-7699-0173
Additional Information:© 1991 Cold Spring Harbor Laboratory Press. The Authors acknowledge that six months after the full-issue publication date, the Article will be distributed under a Creative Commons CC-BY-NC License (Attribution-NonCommercial 4.0 International License, Received July 30, 1991; revised version accepted September 2, 1991. We thank S. Clark, G. Beitel, and R. Horvitz for strains containing let-60(n2301 dn), let-60(n1531 dn), and nDp5, and D. Clark and D. Baillie for information on the dpy-20 gene. We thank P. Tzou and Y. Hajdu for their assistance during the study; R. Aroian, G. Beitel, W. Boorstein, J. Colicelli, A. Golden, I. Greenwald, G. Jongeward, W. Katz, P. Kayne, H. Lipshitz, and S. Parkhust for comments on the manuscript; and H. Bourne, F. McCormick, S. Powers, and members of our laboratory for helpful discussions. Some nematode strains used in this study were provided by the Caenorhabditis Genetic Center, which is funded by the National Institutes of Health National Center for Research Resources (NCRR). M.H. was a Genentech Fellow of the Life Science Research Foundation and is a Lucille P. Markey Scholar in Biomedical Science. P.W.S. is an investigator of the Howard Hughes Medical Institute. This research has been supported by grants to P.W.S. from the U.S. Public Health Service and March of Dimes Birth Defects Foundation. The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.
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Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Life Sciences Research FoundationUNSPECIFIED
Lucille P. Markey Charitable TrustUNSPECIFIED
March of Dimes Birth Defects FoundationUNSPECIFIED
Subject Keywords:ras; Caenorhabditis elegans; dominant-negative mutations; vulval induction
Issue or Number:12a
Record Number:CaltechAUTHORS:20170408-154353782
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:76057
Deposited By: 1Science Import
Deposited On:19 May 2017 21:40
Last Modified:15 Nov 2021 16:57

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