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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

  1. Author:
    Himmel, K. L.
    Bi, F.
    Shen, H. F.
    Jenkins, N. A.
    Copeland, N. G.
    Zheng, Y.
    Largaespada, D. A.

  2. Author Address

    Univ Minnesota, Ctr Canc, Inst Human Genet, Minneapolis, MN 55455 USA Univ Minnesota, Ctr Canc, Inst Human Genet, Minneapolis, MN 55455 USA Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA Univ Tennessee, Ctr Hlth Sci, Dept Mol Sci, Memphis, TN 38163 USA NCI, Frederick Canc Res & Dev Ctr, Mouse Canc Genet Program, Frederick, MD 21702 USA Largaespada DA Univ Minnesota, Ctr Canc, Inst Human Genet, Minneapolis, MN 55455 USA
    1. Year: 2002
  2. Journal: Journal of Biological Chemistry
    1. 277
    2. 16
    3. Pages: 13463-13472
  4. Type of Article: Article
  1. Abstract:

    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 Db1 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 Db1/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.

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