Activation of Clg, a Novel Dbl Family Guanine Nucleotide Exchange Factor Gene, by Proviral Insertion atEvi24, a Common Integration Site in B Cell and Myeloid Leukemias
In: Journal of Biological Chemistry, Jg. 277 (2002-04-01), S. 13463-13472
Online
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Zugriff:
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 geneClg (common-site lymphoma/leukemiaguanine 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 atEvi24. Clg contains Dbl/pleckstrin homology domains with substantial sequence homology to many Rho family activators, including the transforming Dbl andDbs/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 ofEVI24 is located in a region of 19q13 frequently amplified in B cell lymphomas and pancreatic and breast cancers implicateClg and Cdc42 activation in mouse and human cancers.
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Activation of Clg, a Novel Dbl Family Guanine Nucleotide Exchange Factor Gene, by Proviral Insertion atEvi24, a Common Integration Site in B Cell and Myeloid Leukemias
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Autor/in / Beteiligte Person: | Largaespada, David A. ; Zheng, Yi ; Shen, Haifa ; Bi, Feng ; Himmel, Karen L. ; Copeland, Neal G. ; Jenkins, Nancy A. |
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Zeitschrift: | Journal of Biological Chemistry, Jg. 277 (2002-04-01), S. 13463-13472 |
Veröffentlichung: | Elsevier BV, 2002 |
Medientyp: | unknown |
ISSN: | 0021-9258 (print) |
DOI: | 10.1074/jbc.m110981200 |
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