DOMINANT NEGATIVE MUTATIONS OF RAS ONCOGENES

Important note: Information in this article was accurate in 1991. The state of the art may have changed since the publication date.

DOMINANT NEGATIVE MUTATIONS OF RAS ONCOGENES

Adv Applied Biotechnol Ser; 6:77-91 1990. Unique Identifier : AIDSLINE ICDB/91677161
Shih TY; Ogiso Y; Gutierrez L; Wrathall LS; Hwang YW; Lab. of Molecular Oncology, NCI, Frederick, MD 21701-1013

Abstract: A general approach to elucidate the cellular function of a molecularly cloned regulatory gene is to construct dominant negative mutants capable of functional inactivation of the resident wild type gene when introduced into a recipient cell. Regulatory molecules in general possess at least two functional domains for receiving input control signals and for transmitting these signals to output effectors. The rationale for construction of dominant negative mutations based on protein sequence homology and other structural information of the active sites is discussed, with example of the construction of guanosine triphosphate (GTP)-binding site mutants of ras p21. Mutations of the highly conserved sequence motifs at the binding site generated a group of mutant p21s defective in GTP-binding. Some of these mutations activated the oncogenic potential of the proto-oncogenes, although most lost their transforming activities. In this subgroup of transformation-defective H-ras mutants were several interesting mutations that demonstrated a trans-dominant activity of suppressing the transformed phenotype of NIH/3T3 cells induced by a long terminal repeat-linked c-H-ras proto-oncogene. Dominant negative mutants that inhibit the wild type gene function are also described for the p53 tumor suppressor gene and several regulatory genes of human immunodeficiency virus. (44 Refs)

Keywords: Animal Cell Transformation, Neoplastic/*GENETICS *Cloning, Molecular G-Proteins/GENETICS Genes, ras/GENETICS Genes, rev/GENETICS Genes, Dominant/*GENETICS Human HIV-1/GENETICS Mutation/*GENETICS Phenotype Proto-Oncogene Protein p21(ras)/*GENETICS Trans-Activation (Genetics)/PHYSIOLOGY MEETING PAPER REVIEW
912130
M91C4082

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