proto oncogenes


Summary: Normal cellular genes homologous to viral oncogenes. The products of proto-oncogenes are important regulators of biological processes and appear to be involved in the events that serve to maintain the ordered procession through the cell cycle. Proto-oncogenes have names of the form c-onc.

Top Publications

  1. Nitta E, Izutsu K, Yamaguchi Y, Imai Y, Ogawa S, Chiba S, et al. Oligomerization of Evi-1 regulated by the PR domain contributes to recruitment of corepressor CtBP. Oncogene. 2005;24:6165-73 pubmed
    ..These results suggest that oligomerization may contribute to the oncogenic potential of Evi-1-containing proteins. ..
  2. Goyama S, Yamamoto G, Shimabe M, Sato T, Ichikawa M, Ogawa S, et al. Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells. Cell Stem Cell. 2008;3:207-20 pubmed publisher
    ..Thus, Evi-1 is a common and critical regulator essential for proliferation of embryonic/adult HSCs and transformed leukemic cells. ..
  3. Cattaneo F, Nucifora G. EVI1 recruits the histone methyltransferase SUV39H1 for transcription repression. J Cell Biochem. 2008;105:344-52 pubmed publisher
  4. Aytekin M, Vinatzer U, Musteanu M, Raynaud S, Wieser R. Regulation of the expression of the oncogene EVI1 through the use of alternative mRNA 5'-ends. Gene. 2005;356:160-8 pubmed
    ..This induction required transcriptional activity of RNA polymerase, but was also associated with a substantial increase in the stability of these mRNA variants. ..
  5. Ayton P, Cleary M. Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9. Genes Dev. 2003;17:2298-307 pubmed
  6. Nanjundan M, Nakayama Y, Cheng K, Lahad J, Liu J, Lu K, et al. Amplification of MDS1/EVI1 and EVI1, located in the 3q26.2 amplicon, is associated with favorable patient prognosis in ovarian cancer. Cancer Res. 2007;67:3074-84 pubmed
    ..Collectively, these studies suggest that MDS1/EVI1 and EVI1, previously implicated in acute myelogenous leukemia, contribute to the pathophysiology of epithelial ovarian cancer. ..
  7. Senyuk V, Sinha K, Li D, Rinaldi C, Yanamandra S, Nucifora G. Repression of RUNX1 activity by EVI1: a new role of EVI1 in leukemogenesis. Cancer Res. 2007;67:5658-66 pubmed
  8. Calmels B, Ferguson C, Laukkanen M, Adler R, Faulhaber M, Kim H, et al. Recurrent retroviral vector integration at the Mds1/Evi1 locus in nonhuman primate hematopoietic cells. Blood. 2005;106:2530-3 pubmed
    ..Characterization of integration sites in this relevant preclinical model provides critical information for gene therapy risk assessment as well as identification of genes controlling hematopoiesis. ..
  9. Yatsula B, Lin S, Read A, Poholek A, Yates K, Yue D, et al. Identification of binding sites of EVI1 in mammalian cells. J Biol Chem. 2005;280:30712-22 pubmed
    ..In this study we demonstrated for the first time that the N-terminal DNA binding domain of EVI1 has the capacity to bind to endogenous genes. We hypothesized that these genes play a critical role in EVI1-induced transformation. ..

More Information


  1. Buonamici S, Chakraborty S, Senyuk V, Nucifora G. The role of EVI1 in normal and leukemic cells. Blood Cells Mol Dis. 2003;31:206-12 pubmed
  2. So C, Lin M, Ayton P, Chen E, Cleary M. Dimerization contributes to oncogenic activation of MLL chimeras in acute leukemias. Cancer Cell. 2003;4:99-110 pubmed
    ..Our studies support an oligomerization-dependent mechanism for oncogenic conversion of MLL, presumably in part by recruitment of accessory factors through the dimerized MLL moiety of the chimeric protein. ..
  3. Watanabe Okochi N, Kitaura J, Ono R, Harada H, Harada Y, Komeno Y, et al. AML1 mutations induced MDS and MDS/AML in a mouse BMT model. Blood. 2008;111:4297-308 pubmed publisher
    ..Thus, we have developed a useful mouse model of MDS/AML that should help in the understanding of the molecular basis of MDS and the progression of MDS to overt leukemia. ..
  4. Haas K, Kundi M, Sperr W, Esterbauer H, Ludwig W, Ratei R, et al. Expression and prognostic significance of different mRNA 5'-end variants of the oncogene EVI1 in 266 patients with de novo AML: EVI1 and MDS1/EVI1 overexpression both predict short remission duration. Genes Chromosomes Cancer. 2008;47:288-98 pubmed publisher
    ..This article contains Supplementary Material available at ..
  5. Sato T, Goyama S, Nitta E, Takeshita M, Yoshimi M, Nakagawa M, et al. Evi-1 promotes para-aortic splanchnopleural hematopoiesis through up-regulation of GATA-2 and repression of TGF-b signaling. Cancer Sci. 2008;99:1407-13 pubmed publisher
    ..Our findings suggest that Evi-1 promotes hematopoietic stem/progenitor expansion at the embryonic stage through up-regulation of GATA-2 and repression of TGF-beta signaling. ..
  6. Williams D, Baum C. Medicine. Gene therapy--new challenges ahead. Science. 2003;302:400-1 pubmed
    ..reinforces the need to develop even more specific gene therapy interventions. ..
  7. Konrad T, Karger A, Hackl H, Schwarzinger I, Herbacek I, Wieser R. Inducible expression of EVI1 in human myeloid cells causes phenotypes consistent with its role in myelodysplastic syndromes. J Leukoc Biol. 2009;86:813-22 pubmed publisher
    ..In summary, these data show that inducible expression of EVI1 in U937 cells causes phenotypes that may be relevant for its role in MDS and provides a basis for further investigation of its contribution to this fatal disease. ..
  8. Spensberger D, Delwel R. A novel interaction between the proto-oncogene Evi1 and histone methyltransferases, SUV39H1 and G9a. FEBS Lett. 2008;582:2761-7 pubmed publisher
    ..In addition, Evi1 also interacts with another histone methyltransferase, G9a, but not with SET9. Our data establish an epigenetic role of Evi1 in cell transformation by recruiting higher order chromatin remodeling complexes. ..
  9. Uren A, Kool J, Berns A, van Lohuizen M. Retroviral insertional mutagenesis: past, present and future. Oncogene. 2005;24:7656-72 pubmed
  10. Nucifora G, Laricchia Robbio L, Senyuk V. EVI1 and hematopoietic disorders: history and perspectives. Gene. 2006;368:1-11 pubmed
    ..In this review, we summarize the biochemical properties of EVI1 and the effects of EVI1 in biological models. ..
  11. Buonamici S, Li D, Mikhail F, Sassano A, Platanias L, Colamonici O, et al. EVI1 abrogates interferon-alpha response by selectively blocking PML induction. J Biol Chem. 2005;280:428-36 pubmed
    ..These results point to a novel mechanism utilized by an oncogene to escape normal cell response to growth-controlling cytokines. ..
  12. Liu Y, Chen L, Ko T, Fields A, Thompson E. Evi1 is a survival factor which conveys resistance to both TGFbeta- and taxol-mediated cell death via PI3K/AKT. Oncogene. 2006;25:3565-75 pubmed
    ..These data indicate that Evi1 functions as a survival gene in intestinal epithelial cells and colon cancer cells, activating PI3K/AKT and conveying resistance to both physiological and therapeutic apoptotic stimuli. ..
  13. Lugthart S, van Drunen E, van Norden Y, van Hoven A, Erpelinck C, Valk P, et al. High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated. Blood. 2008;111:4329-37 pubmed publisher
    ..001 and event-free survival [EFS]: P = .002). We argue that EVI1/ME quantitative expression analysis should be implemented in the molecular diagnostic procedures of AML. ..
  14. Wieser R. The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Gene. 2007;396:346-57 pubmed
    ..This review summarizes the currently available experimental evidence for the proposed biochemical and biological functions of this important oncogene. ..
  15. Rimann I, Hajnal A. Regulation of anchor cell invasion and uterine cell fates by the egl-43 Evi-1 proto-oncogene in Caenorhabditis elegans. Dev Biol. 2007;308:187-95 pubmed
    ..Comparison with mammalian Evi-1 suggests a conserved pathway controlling cell invasion and cell fate specification. ..
  16. Eddy J, Maizels N. Gene function correlates with potential for G4 DNA formation in the human genome. Nucleic Acids Res. 2006;34:3887-96 pubmed
    ..Selection based on G4P could promote genomic stability (or instability) of specific classes of genes; or reflect mechanisms for global regulation of gene expression. ..
  17. Modlich U, Schambach A, Brugman M, Wicke D, Knoess S, Li Z, et al. Leukemia induction after a single retroviral vector insertion in Evi1 or Prdm16. Leukemia. 2008;22:1519-28 pubmed publisher
    ..Our study also shows that insertional mutagenesis is required for leukemia induction by IL2RG vectors, a risk to be addressed by improved vector design...
  18. Chi Y, Senyuk V, Chakraborty S, Nucifora G. EVI1 promotes cell proliferation by interacting with BRG1 and blocking the repression of BRG1 on E2F1 activity. J Biol Chem. 2003;278:49806-11 pubmed
    ..Taken together, these data support the hypothesis that the interaction with BRG1 is important for up-regulation of cell-growth by EVI1. ..
  19. Furney S, Madden S, Kisiel T, Higgins D, Lopez Bigas N. Distinct patterns in the regulation and evolution of human cancer genes. In Silico Biol. 2008;8:33-46 pubmed
    ..A number of these trends are confirmed in breast and colon cancer gene sets recently identified by mutational screening. ..
  20. Hsieh J, Cheng E, Korsmeyer S. Taspase1: a threonine aspartase required for cleavage of MLL and proper HOX gene expression. Cell. 2003;115:293-303 pubmed
    ..Taspase1 coevolved with MLL/trithorax as Arthropoda and Chordata emerged from Metazoa suggesting that Taspase1 originated to regulate complex segmental body plans in higher organisms. ..
  21. Poppe B, Dastugue N, Vandesompele J, Cauwelier B, De Smet B, Yigit N, et al. EVI1 is consistently expressed as principal transcript in common and rare recurrent 3q26 rearrangements. Genes Chromosomes Cancer. 2006;45:349-56 pubmed
    ..Our results underscore the feasibility of FISH as an adjunct to PCR for the identification of EVI1 deranged leukemias and identified EVI1 as the principal transcript expressed in these malignancies. ..
  22. Mitani K. Molecular mechanisms of leukemogenesis by AML1/EVI-1. Oncogene. 2004;23:4263-9 pubmed
    ..All these functions cooperatively contribute to the malignant transformation of the hematopoietic stem cells by AML1/EVI-1. ..
  23. Buonamici S, Li D, Chi Y, Zhao R, Wang X, Brace L, et al. EVI1 induces myelodysplastic syndrome in mice. J Clin Invest. 2004;114:713-9 pubmed
    ..These defects are not fatal, and the mice survive for about 10 months with compensated hematopoiesis. Over this time, compensation fails, and the mice succumb to fatal peripheral cytopenia. ..
  24. Jin G, Yamazaki Y, Takuwa M, Takahara T, Kaneko K, Kuwata T, et al. Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis. Blood. 2007;109:3998-4005 pubmed
    ..Furthermore, Trib1 by itself is a novel myeloid oncogene, enhancing phosphorylation of ERK, resulting in inhibition of apoptosis. These results demonstrate the importance of specific oncogene interaction in myeloid leukemogenesis. ..
  25. Du Y, Jenkins N, Copeland N. Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells. Blood. 2005;106:3932-9 pubmed
    ..Genes identified by insertional mutagenesis by their nature could also be involved in immortalization of leukemic stem cells, and thus represent attractive drug targets for treating cancer. ..
  26. Morishita K. Leukemogenesis of the EVI1/MEL1 gene family. Int J Hematol. 2007;85:279-86 pubmed
    ..The functions of EVI1/MEL1 members as transcription factors and the concept of EVI1-positive leukemia as a stem cell disease are also reviewed. ..
  27. De Weer A, Speleman F, Cauwelier B, Van Roy N, Yigit N, Verhasselt B, et al. EVI1 overexpression in t(3;17) positive myeloid malignancies results from juxtaposition of EVI1 to the MSI2 locus at 17q22. Haematologica. 2008;93:1903-7 pubmed publisher
    ..In keeping with findings in other recurrent 3q26 rearrangements, overexpression of the EVI1 gene appears to be the major contributor to leukemogenesis in patients with a t(3;17). ..
  28. Maeda T, Hobbs R, Merghoub T, Guernah I, Zelent A, Cordon Cardo C, et al. Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature. 2005;433:278-85 pubmed
    ..Pokemon's critical role in cellular transformation makes it an attractive target for therapeutic intervention. ..
  29. Cuenco G, Ren R. Both AML1 and EVI1 oncogenic components are required for the cooperation of AML1/MDS1/EVI1 with BCR/ABL in the induction of acute myelogenous leukemia in mice. Oncogene. 2004;23:569-79 pubmed
    ..The results indicate that both the AML1 and EVI1 oncogenic components are required for the leukemogenic potential of AME and for the cooperation of AME and BCR/ABL in the induction of AML. ..
  30. Martin M, Milne T, Bloyer S, Galoian K, Shen W, Gibbs D, et al. Dimerization of MLL fusion proteins immortalizes hematopoietic cells. Cancer Cell. 2003;4:197-207 pubmed
    ..However, MLL-AF9 is not dimerized in vivo. The data support a model in which either MLL dimerization/exon duplication or fusion to a transcriptional activator results in Hox gene upregulation and ultimately transformation. ..
  31. Yuasa H, Oike Y, Iwama A, Nishikata I, Sugiyama D, Perkins A, et al. Oncogenic transcription factor Evi1 regulates hematopoietic stem cell proliferation through GATA-2 expression. EMBO J. 2005;24:1976-87 pubmed
    ..Our results reveal that GATA-2 is presumably one of critical targets for Evi1 and that transcription factors regulate the HSC pool hierarchically. ..
  32. Palmer S, Brouillet J, Kilbey A, Fulton R, Walker M, Crossley M, et al. Evi-1 transforming and repressor activities are mediated by CtBP co-repressor proteins. J Biol Chem. 2001;276:25834-40 pubmed
  33. Shimizu S, Nagasawa T, Katoh O, Komatsu N, Yokota J, Morishita K. EVI1 is expressed in megakaryocyte cell lineage and enforced expression of EVI1 in UT-7/GM cells induces megakaryocyte differentiation. Biochem Biophys Res Commun. 2002;292:609-16 pubmed
  34. Nordgren A, Heyman M, Sahlén S, Schoumans J, Soderhall S, Nordenskjold M, et al. Spectral karyotyping and interphase FISH reveal abnormalities not detected by conventional G-banding. Implications for treatment stratification of childhood acute lymphoblastic leukaemia: detailed analysis of 70 cases. Eur J Haematol. 2002;68:31-41 pubmed
    ..Our results demonstrate the usefulness of SKY and interphase FISH for the identification of novel chromosome aberrations and cytogenetic abnormalities that provide prognostically important information in childhood ALL. ..
  35. Van Roy N, Vandesompele J, Berx G, Staes K, Van Gele M, De Smet E, et al. Localization of the 17q breakpoint of a constitutional 1;17 translocation in a patient with neuroblastoma within a 25-kb segment located between the ACCN1 and TLK2 genes and near the distal breakpoints of two microdeletions in neurofibromatosis type . Genes Chromosomes Cancer. 2002;35:113-20 pubmed
  36. Smith M, Wang Y, Skibola C, Slater D, Lo Nigro L, Nowell P, et al. Low NAD(P)H:quinone oxidoreductase activity is associated with increased risk of leukemia with MLL translocations in infants and children. Blood. 2002;100:4590-3 pubmed
    ..The inactivating NQO1 polymorphism is associated with an increased risk of de novo leukemia with MLL translocations in infants and children. ..
  37. Yokoyama A, Kitabayashi I, Ayton P, Cleary M, Ohki M. Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties. Blood. 2002;100:3710-8 pubmed
    ..These observations suggest that posttranslational modifications of MLL may participate in regulating its activity as a transcription factor and that this aspect of its function is perturbed by leukemogenic fusions. ..
  38. Rozovskaia T, Feinstein E, Mor O, Foa R, Blechman J, Nakamura T, et al. Upregulation of Meis1 and HoxA9 in acute lymphocytic leukemias with the t(4 : 11) abnormality. Oncogene. 2001;20:874-8 pubmed
    ..The present work suggests that upregulation of Meis1, HoxA9, and possibly HoxA10 might also play a role in pathogenesis of acute lymphocytic and acute myeloid leukemias associated with ALL-1 fusions. ..
  39. Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti R, Kuppers R, et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature. 2001;412:341-6 pubmed
    ..By mutating multiple genes, and possibly by favouring chromosomal translocations, aberrant hypermutation may represent the major contributor to lymphomagenesis. ..
  40. Vinatzer U, Taplick J, Seiser C, Fonatsch C, Wieser R. The leukaemia-associated transcription factors EVI-1 and MDS1/EVI1 repress transcription and interact with histone deacetylase. Br J Haematol. 2001;114:566-73 pubmed
    ..This interaction can be recapitulated in vitro and is mediated by a previously characterized transcription repression domain, whose activity is alleviated by the histone deacetylase inhibitor trichostatin A. ..
  41. Ayton P, Cleary M. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene. 2001;20:5695-707 pubmed
    ..We discuss potential mechanisms that may account for the ability of distinct MLL fusion proteins to promote short or long latency leukemogenesis. ..
  42. Armstrong S, Staunton J, Silverman L, Pieters R, den Boer M, Minden M, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet. 2002;30:41-7 pubmed
    ..Establishing that MLL is a unique entity is critical, as it mandates the examination of selectively expressed genes for urgently needed molecular targets. ..
  43. Barjesteh van Waalwijk van Doorn Khosrovani S, Erpelinck C, van Putten W, Valk P, van der Poel van de Luytgaarde S, Hack R, et al. High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Blood. 2003;101:837-45 pubmed
    ..Our data demonstrate that high EVI1 expression is an independent poor prognostic marker within the intermediate- risk karyotypic group. ..
  44. Milne T, Briggs S, Brock H, Martin M, Gibbs D, Allis C, et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell. 2002;10:1107-17 pubmed
    ..A leukemogenic MLL fusion protein that activates Hox expression had no effect on histone methylation, suggesting a distinct mechanism for gene regulation by MLL and MLL fusion proteins. ..
  45. Nakamura T, Mori T, Tada S, Krajewski W, Rozovskaia T, Wassell R, et al. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol Cell. 2002;10:1119-28 pubmed
    ..In parallel, H3-K4 is methylated, and histones H3 and H4 are acetylated at this promoter. ..
  46. Vinatzer U, Mannhalter C, Mitterbauer M, Gruener H, Greinix H, Schmidt H, et al. Quantitative comparison of the expression of EVI1 and its presumptive antagonist, MDS1/EVI1, in patients with myeloid leukemia. Genes Chromosomes Cancer. 2003;36:80-9 pubmed
    ..We further provide preliminary evidence that the RTQ-RT-PCR assay may be useful for disease monitoring in patients overexpressing EVI1. ..
  47. So C, Karsunky H, Passegue E, Cozzio A, Weissman I, Cleary M. MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice. Cancer Cell. 2003;3:161-71 pubmed
    ..This experimental modeling of ABL in mice highlights its origin from multipotential progenitors that arrest at a bipotential stage specifically targeted or induced by MLL oncogenes. ..
  48. Chakraborty S, Senyuk V, Sitailo S, Chi Y, Nucifora G. Interaction of EVI1 with cAMP-responsive element-binding protein-binding protein (CBP) and p300/CBP-associated factor (P/CAF) results in reversible acetylation of EVI1 and in co-localization in nuclear speckles. J Biol Chem. 2001;276:44936-43 pubmed
    ..Finally, we show that the interaction of EVI1 with either CBP or P/CAF leads to acetylation of EVI1. These results suggest that the assembly of EVI1 in nuclear speckles requires the intact HAT activity of the co-activators. ..
  49. Izutsu K, Kurokawa M, Imai Y, Maki K, Mitani K, Hirai H. The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling. Blood. 2001;97:2815-22 pubmed
    ..This identifies a novel function of Evi-1 as a member of corepressor complexes and suggests that aberrant recruitment of corepressors is one of the mechanisms for Evi-1-induced leukemogenesis. ..
  50. Hayashi Y. [Recent progress of molecular diagnosis in pediatric malignancies]. Gan To Kagaku Ryoho. 2003;30:1211-24 pubmed
    ..These advances have led to the increased importance of molecular diagnosis as well as morphological diagnosis. We review here the recent progress of molecular diagnosis in pediatric malignancies. ..
  51. Douet Guilbert N, Morel F, LE Bris M, Sassolas B, Giroux J, de Braekeleer M. Rearrangement of MLL in a patient with congenital acute monoblastic leukemia and granulocytic sarcoma associated with a t(1;11)(p36;q23) translocation. Leuk Lymphoma. 2005;46:143-6 pubmed
    ..To the best of our knowledge, this is the first report of a case of congenital AML with GS arising in a patient with proven MLL rearrangement. ..
  52. Bogni A, Pui C, Relling M. MLL methylation is not likely a common mechanism for therapy-related AML. Leukemia. 2005;19:1291-2 pubmed
  53. Alliston T, Ko T, Cao Y, Liang Y, Feng X, Chang C, et al. Repression of bone morphogenetic protein and activin-inducible transcription by Evi-1. J Biol Chem. 2005;280:24227-37 pubmed
    ..In this way, Evi-1 acts as a general Smad corepressor to inhibit TGF-beta-, activin-, and BMP-inducible transcription. ..