1: EMBO J. 2000 Jun 15;19(12):2958-68. 

The evi-1 oncoprotein inhibits c-Jun N-terminal kinase and prevents
stress-induced cell death.

Kurokawa M, Mitani K, Yamagata T, Takahashi T, Izutsu K, Ogawa S, Moriguchi T,
Nishida E, Yazaki Y, Hirai H.

Department of Hematology and Oncology, Graduate School of Medicine, University
of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Evi-1 encodes a nuclear protein involved in leukemic transformation of
hematopoietic cells. Evi-1 possesses two sets of zinc finger motifs separated
into two domains, and its characteristics as a transcriptional regulator have
been described. Here we show that Evi-1 acts as an inhibitor of c-Jun N-terminal
kinase (JNK), a class of mitogen-activated protein kinases implicated in stress
responses of cells. Evi-1 physically interacts with JNK, although it does not
affect its phosphorylation. This interaction is required for inhibition of JNK.
Evi-1 protects cells from stress-induced cell death with dependence on the
ability to inhibit JNK. These results reveal a novel function of Evi-1, which
provides evidence for inhibition of JNK by a nuclear oncogene product. Evi-1
blocks cell death by selectively inhibiting JNK, thereby contributing to
oncogenic transformation of cells.

PMID: 10856240 [PubMed - indexed for MEDLINE]


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2: Oncogene. 1995 Sep 7;11(5):833-40. 

The AML1/Evi-1 fusion protein in the t(3;21) translocation exhibits transforming
activity on Rat1 fibroblasts with dependence on the Evi-1 sequence.

Kurokawa M, Ogawa S, Tanaka T, Mitani K, Yazaki Y, Witte ON, Hirai H.

Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo,
Japan.

The t(3;21) (q26;q22) chromosomal translocation associated with blastic crisis
of chronic myelogenous leukemia (CML) results in the formation of a chimeric
protein fusing the amino-terminal DNA-binding domain encoded by the AML1 gene to
the carboxyl-terminal-encoding portion of the Evi-1 gene. In order to evaluate
transforming activity of this protein, AML1/Evi-1 was introduced into Rat1
fibroblasts. Cells expressing the fusion product formed macroscopic colonies in
soft agar, indicating that AML1/Evi-1 is a transforming gene. It was also
demonstrated that introduction of AML1/Evi-1 into the Rat1 clones harboring
BCR/ABL also conferred enhanced capacity for anchorage independent growth.
Analyses of deletion mutants of AML1/Evi-1 revealed that removal of the second
zinc finger domain within the Evi-1 sequence totally abrogated the ability of
AML1/Evi-1 to transform Rat1 cells. We showed that the transforming effect is
correlated with the AP-1 activation induced by AML1/Evi-1. Furthermore, we
demonstrated that c-jun is transcriptionally activated in Rat1 cells transformed
by AML1/Evi-1, suggesting that c-jun expression is under control of AML1/Evi-1.
These results indicate that the oncogenic effect of the t(3;21) translocation is
caused by the generation of a chimeric transcriptional factor and that
AML1/Evi-1 could perform a pivotal role in leukemic progression of CML.

PMID: 7675444 [PubMed - indexed for MEDLINE]


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3: J Biol Chem. 1994 Sep 30;269(39):24020-6. 

Evi-1 raises AP-1 activity and stimulates c-fos promoter transactivation with
dependence on the second zinc finger domain.

Tanaka T, Nishida J, Mitani K, Ogawa S, Yazaki Y, Hirai H.

Department of Molecular Biology, Jichi Medical School, Tochigi, Japan.

Evi-1 is a gene, encoding a zinc finger protein, associated with a common viral
integration site in murine leukemias. It is suggested that Evi-1 plays important
roles in embryogenesis and transformation of myeloid cells. To elucidate
mechanisms by which Evi-1 induces such biological effects, we analyzed the
relationship between Evi-1 and AP-1 which could regulate cellular proliferation
and differentiation. When Evi-1 was expressed, transactivation through a
12-O-tetradecanoylphorbol 13-acetate-responsive element was observed in NIH3T3
and P19 cells. Evi-1-transfected P19 cells showed some differentiated phenotypes
and increased expression of endogenous c-Jun and c-Fos. These results indicate
that Evi-1 raises AP-1 activity. Evi-1 caused stimulation of the c-fos promoter
transactivation, which seems to be a main mechanism of AP-1 activation, through
at least two portions of the promoter. Evi-1 has the first zinc finger domain at
the N terminus and the second zinc finger domain near the C-terminus. We
constructed deletion mutants of Evi-1 and investigated the functions of these
domains. It was shown that the second zinc finger domain is essential for the
activation of AP-1 and transactivation of the c-fos promoter.

PMID: 7929053 [PubMed - indexed for MEDLINE]


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