Dominant-negative mutations in PPAR alpha are present in unselected human populations and have a metabolic signature

Key Points Monoallelic STXBP2 mutations affecting codon 65 impair lymphocyte cytotoxicity and contribute to hemophagocytic lymphohistiocytosis. Munc18-2R65Q/W mutant proteins function in a dominant-negative manner to impair membrane fusion and arrest SNARE-complex assembly.

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Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome

Nature ◽

10.1038/nature06096 ◽

2007 ◽

Vol 448 (7157) ◽

pp. 1058-1062 ◽

Cited By ~ 683

Author(s):

Yoshiyuki Minegishi ◽

Masako Saito ◽

Shigeru Tsuchiya ◽

Ikuya Tsuge ◽

Hidetoshi Takada ◽

...

Keyword(s):

Dna Binding ◽

Binding Domain ◽

Dominant Negative ◽

Dna Binding Domain ◽

Hyper Ige Syndrome ◽

Dominant Negative Mutations

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Functional inactivation of genes by dominant negative mutations

Nature ◽

10.1038/329219a0 ◽

1987 ◽

Vol 329 (6136) ◽

pp. 219-222 ◽

Cited By ~ 664

Author(s):

Ira Herskowitz

Keyword(s):

Dominant Negative ◽

Dominant Negative Mutations ◽

Functional Inactivation

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The erbA oncogene represses the actions of both retinoid X and retinoid A receptors but does so by distinct mechanisms

Molecular and Cellular Biology ◽

10.1128/mcb.13.10.5970-5980.1993 ◽

1993 ◽

Vol 13 (10) ◽

pp. 5970-5980

Author(s):

H W Chen ◽

M L Privalsky

Keyword(s):

Thyroid Hormone ◽

Hormone Receptors ◽

Thyroid Hormone Receptor ◽

Dominant Negative ◽

Nuclear Hormone Receptors ◽

Dominant Negative Inhibitor ◽

Dominant Negative Mutations ◽

Microbial Systems ◽

Dna Binding Properties ◽

Activate Gene

Genetic lesions that function as dominant negative mutations in microbial systems have long been recognized. It is only relatively recently, however, that similar dominant negative mutations have been implicated as a basis for genetic and neoplastic disorders in vertebrates. We describe here a dissection of the actions of the erbA oncogene protein, an aberrant form of thyroid hormone receptor that acts as a dominant negative inhibitor of other nuclear hormone receptors. We demonstrate that the ErbA oncoprotein interferes with thyroid hormone and trans-retinoic acid receptors by competing for binding to the corresponding response elements. Heterodimerization of the ErbA oncoprotein with these receptors does not play an observable role in repression. In contrast, however, the ErbA oncoprotein does efficiently form a heterodimer with the retinoid X receptor (RXR) class of nuclear hormone receptors; complex formation enhances the DNA-binding properties of the ErbA protein but dramatically interferes with the ability of the RXR component to activate gene expression. Our results indicate that the erbA oncogene may play a previously unanticipated role in neoplasia by interfering with RXR function.

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Caenorhabditis elegans SUR-5, a Novel but Conserved Protein, Negatively Regulates LET-60 Ras Activity during Vulval Induction

Molecular and Cellular Biology ◽

10.1128/mcb.18.8.4556 ◽

1998 ◽

Vol 18 (8) ◽

pp. 4556-4564 ◽

Cited By ~ 88

Author(s):

Trent Gu ◽

Satoshi Orita ◽

Min Han

Keyword(s):

Caenorhabditis Elegans ◽

Sequence Similarity ◽

Signal Transduction Pathway ◽

Specific Aspect ◽

Dominant Negative ◽

Loss Of Function ◽

Negative Function ◽

Ras Activation ◽

Dominant Negative Mutations ◽

Novel Protein

ABSTRACT The let-60 ras gene acts in a signal transduction pathway to control vulval differentiation in Caenorhabditis elegans. By screening suppressors of a dominant negativelet-60 ras allele, we isolated three loss-of-function mutations in the sur-5 gene which appear to act as negative regulators of let-60 ras during vulval induction.sur-5 mutations do not cause an obvious mutant phenotype of their own, and they appear to specifically suppress only one of the two groups of let-60 ras dominant negative mutations, suggesting that the gene may be involved in a specific aspect of Ras activation. Consistent with its negative function, overexpressing sur-5 from an extragenic array partially suppresses the Multivulva phenotype of an activatedlet-60 ras mutation and causes synergistic phenotypes with a lin-45 raf mutation. We have clonedsur-5 and shown that it encodes a novel protein. We have also identified a potential mammalian SUR-5 homolog that is about 35% identical to the worm protein. SUR-5 also has some sequence similarity to acetyl coenzyme A synthetases and is predicted to contain ATP/GTP and AMP binding sites. Our results suggest thatsur-5 gene function may be conserved through evolution.

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