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.
Himmel
Karen L
KL
University of Minnesota Cancer Center, Institute of Human Genetics, Department of Genetics, University of Minnesota, Minneapolis 55455, USA.
Bi
Feng
F
Shen
Haifa
H
Jenkins
Nancy A
NA
Copeland
Neal G
NG
Zheng
Yi
Y
Largaespada
David A
DA
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D019556:COS Cells; D002888:Chromosomes, Human, Pair 19; D003001:Cloning, Molecular; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015448:Leukemia, B-Cell / Q000235:genetics / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010802:Phylogeny; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012190:Retroviridae / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013997:Time Factors; D014018:Tissue Distribution; D014162:Transfection
C455620:Clg protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C057811:MCF2 protein, human; C512843:Mcf2 protein, mouse; D011518:Proto-Oncogene Proteins; D008156:Luciferases