Activation of clg, a novel dbl family guanine nucleotide exchange factor gene, by proviral insertion at evi24, a common integration site in B cell and myeloid leukemias.
Retroviruses induce leukemia in inbred strains of mice by activating cellular proto-oncogenes and/or inactivating tumor suppressors. The proviral integration sites in these leukemias provide powerful genetic tags for disease gene identification. Here we show that Evi24, a common site of retroviral integration in AKXD B cell and BXH-2 myeloid leukemias, ... contains a novel Dbl family guanine nucleotide exchange factor gene. We have designated this gene Clg (common-site lymphoma/leukemia guanine nucleotide exchange factor). Proviral integrations on chromosome 7 at Evi24 are located 7.6-10.3 kb upstream of Clg and increased Clg expression 2-5-fold compared with leukemias lacking proviral integrations at Evi24. Clg contains Dbl/pleckstrin homology domains with substantial sequence homology to many Rho family activators, including the transforming Dbl and Dbs/Ost oncogenes. Nucleotide exchange assays indicated that Clg specifically activated nucleotide exchange on Cdc42, but not RhoA or Rac1, in vitro. NIH 3T3 transfection studies showed that overexpression of full-length and carboxyl-terminally truncated forms of Clg morphologically transformed NIH 3T3 cells. This study and studies showing that the human homolog of EVI24 is located in a region of 19q13 frequently amplified in B cell lymphomas and pancreatic and breast cancers implicate Clg and Cdc42 activation in mouse and human cancers.
Mesh Terms:
3T3 Cells, Amino Acid Sequence, Animals, Base Sequence, Blotting, Northern, Blotting, Southern, Blotting, Western, COS Cells, Chromosomes, Human, Pair 19, Cloning, Molecular, Guanine Nucleotide Exchange Factors, Humans, Leukemia, B-Cell, Leukemia, Myeloid, Luciferases, Mice, Models, Genetic, Molecular Sequence Data, Phylogeny, Protein Structure, Tertiary, Proto-Oncogene Proteins, Retroviridae, Sequence Homology, Amino Acid, Signal Transduction, Time Factors, Tissue Distribution, Transfection
3T3 Cells, Amino Acid Sequence, Animals, Base Sequence, Blotting, Northern, Blotting, Southern, Blotting, Western, COS Cells, Chromosomes, Human, Pair 19, Cloning, Molecular, Guanine Nucleotide Exchange Factors, Humans, Leukemia, B-Cell, Leukemia, Myeloid, Luciferases, Mice, Models, Genetic, Molecular Sequence Data, Phylogeny, Protein Structure, Tertiary, Proto-Oncogene Proteins, Retroviridae, Sequence Homology, Amino Acid, Signal Transduction, Time Factors, Tissue Distribution, Transfection
J. Biol. Chem.
Date: Apr. 19, 2002
PubMed ID: 11839748
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