Important note: Information in this article was accurate in 1990. The state of the art may have changed since the publication date.
FUNCTIONAL DOMAINS OF THE C-ABL PROTEIN TYROSINE KINASE
Diss Abstr Int [B]; 51(3):1119 1990. Unique Identifier : AIDSLINE ICDB/90668532 Jackson PK; Harvard Univ.
Abstract:
Abelson murine leukemia virus is an oncogenic retrovirus capable of inducing a pre-B cell leukemia. The transforming ability of Abelson virus requires its gene product, pp160v-(abl), a cytoplasmic tyrosine kinase. Abelson virus can transform bone marrow in vitro and cultured cells, notably fibroblasts. The v-abl gene has a cellular homologue, c-abl. The two forms of c-abl differ from v-abl by replacement of their N-terminal sequences with viral gag sequences. Overexpression of p150c-abl(IV) in a retroviral vector does not transform murine fibroblasts, even though it is expressed and myristoylated similarly to pp160v-abl. In this expression system, deletions of the N-terminus activate c-abl(IV) to transform fibroblasts. The smallest of these deletions, DeltaXB, transforms lymphoid cells in vitro and causes leukemia in vivo. The DeltaXB mutation defines a regulatory domain, called SH3, sharing homology with non-kinase gene products: phospholipase C-II, the oncogene v-crk, and several actin-binding proteins. Overexpression of c-abl(IV) does profoundly inhibit cell growth. The subcellular localization of the c-abl(IV) protein was determined by immunofluorescence of fibroblasts that overexpress the protein. Unlike p160gag-abl, which has cytoplasmic and plasma membrane localization, much of the c-abl (IV) protein is nuclear, the remainder in the cytoplasm and plasma membrane, largely associated with actin stress filaments. Deletion of SH3 in the c-abl (IV) protein changes the distribution of abl from nuclear to cytoplasmic. Mapping of amino acid sequences responsible for nuclear localization in p150c-abl((IV)) reveals a C-terminal signal similar to that of SV40 large T antigen and a second nuclear localization signal further C-terminal. Mutations in the nuclear localization signals do not activate transformation by abl. Thus, these nuclear localization signals play a passive role, allowing the abl protein to be recognized for nuclear transport. The relocalization of the SH3-deleted mutant of c-abl does not depend on the transformed state of the cells, but rather on the loss of SH3 sequences. Nonetheless, SH3 does not appear to function as a nuclear localization signal in other proteins or in isolation. Thus, the SH3 domain appears to globally control the abl protein's ability to transform cells and its cellular localization. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD90-21799)
Keywords: Abelson Leukemia Virus/ENZYMOLOGY/*GENETICS Amino Acid Sequence Animal Cell Transformation, Viral/*GENETICS Gene Products, gag/GENETICS Genes, gag Leukemia, Experimental/*GENETICS Mice Mutation Protein-Tyrosine Kinase/*GENETICS Proto-Oncogene Proteins/*GENETICS THESIS 901230
M90C3720
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Important note: Information in this article was accurate in 1990. The state of the art may have changed since the publication date.
