Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Oncogenic Vav1 induces Rac-dependent apoptosis via inhibition of Bcl-2 family proteins and collaborates with p53 deficiency to promote hematopoietic progenitor cell proliferation

Oncogene volume 25, pages 3963–3972 (2006)Cite this article

Abstract

Vav1 is an hematopoietic-specific Rho guanine nucleotide exchange factor coupling tyrosine kinase receptors and Rac GTPases, and has been implicated in transformation of fibroblasts and pancreas. To determine the biologic effect and oncogenic potential of Vav1 in hematopoietic lineages, we stably express oncogenic mutant of Vav1 in primary bone marrow cells using retrovirus-mediated gene transfer. Contrary to the growth stimulatory effects observed in fibroblasts, oncogenic Vav1 inhibits hematopoietic stem cell/progenitor engraftment in vivo and progenitor cell expansion in vitro via inducing apoptosis. The oncogenic Vav1-induced apoptosis is associated with reduced expression of Bcl-2 and Bcl-xL proteins and effectively suppressed by transgenic overexpression of Bcl-2, suggesting Vav1-mediated signaling via Bcl-2 in apoptosis. Also, oncogenic Vav1 stimulates sustained activation of Rac GTPases and the biologic effects of oncogenic Vav1 are Rac-dependent. Further, when expressed in the p53-deficient cells, which express elevated Bcl-2 and Bcl-xL and are resistant to the apoptosis, oncogenic Vav1 enhances both proliferation and self-renewal of hematopoietic progenitor cells. These results demonstrate clear phenotypic differences between wild-type and p53−/− hematopoietic cells expressing oncogenic Vav1, and suggest oncogenic potential of Vav1-mediated pathways in primary hematopoietic cell when they collaborate with additional genetic hits that affect the p53 pathway.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Aghazadeh B, Lowry WE, Huang XY, Rosen MK . (2000). Cell 102: 625–633.

  • Alai M, Mui AL-F, Cutler RL, Bustolo XR, Barbacid M . (1992). J Biol Chem 267: 18021–18025.

  • Benard V, Bohl BP, Bokoch GM . (1999). J Biol Chem 274: 13198–13204.

  • Betz R, Sandhoff K, Fischer KD, van Echten-Deckert G . (2003). Neurosci Lett 339: 37–40.

  • Bronson SK, Plaehn EG, Kluckman KD, Hagaman JR, Maeda N, Smithies O . (1996). Proc Natl Acad Sci USA 93: 9067–9072.

  • Bustelo XR . (2000). Mol Cell Biol 20: 1461–1477.

  • Crespo P, Schuebel KE, Ostrom AA, Gutkind JS, Bustelo XR . (1997). Nature 385: 169–172.

  • Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y et al. (1997). Cell 91: 231–241.

  • Debreceni B, Gao Y, Guo F, Zhu K, Jia B, Zheng Y . (2004). J Biol Chem 279: 3777–3786.

  • Dibbert B, Daigle I, Braun D, Schranz C, Weber M, Blaser K et al. (1998). Blood 92: 778–783.

  • Diekmann D, Nobes CD, Burbelo PD, Abo A, Hall A . (1995). EMBO J 14: 5297–5305.

  • Esteve P, Embade N, Perona R, Jimenez B, del Peso L, Leon J et al. (1998). Oncogene 17: 1855–1869.

  • Fernandez-Zapico ME, Gonzalez-Paz NC, Weiss E, Savoy DN, Molina JR, Fonseca R et al. (2005). Cancer Cell 7: 39–49.

  • Filippi MD, Harris CE, Meller J, Gu Y, Zheng Y, Williams DA . (2004). Nat Immunol 5: 744–751.

  • Fujikawa K, Miletic AV, Alt FW, Faccio R, Brown T, Hoog J et al. (2003). J Exp Med 198: 1595–1608.

  • Gakidis MA, Cullere X, Olson T, Wilsbacher JL, Zhang B, Moores SL et al. (2004). J Cell Biol 166: 273–282.

  • Gu Y, Filippi MD, Cancelas JA, Siefring JE, Williams EP, Jasti AC et al. (2003). Science 302: 445–449.

  • Gu Y, Jasti AC, Jansen M, Siefring JE . (2005). Blood 105: 1467–1475.

  • Gu Y, Jia B, Yang FC, D’Souza M, Harris CE, Derrow CW et al. (2001). J Biol Chem 276: 15929–15938.

  • Han J, Das B, Wei W, Van Aelst L, Mosteller RD, Khosravi-Far R et al. (1997). Mol Cell Biol 17: 1346–1353.

  • Hanenberg H, Hashino K, Konishi H, Hock RA, Kato I, Williams DA . (1997). Hum Gene Ther 8: 2193–2206.

  • Hornstein I, Pikarsky E, Groysman M, Amir G, Peylan-Ramu N, Katzav S . (2003). J Pathol 199: 526–533.

  • Joneson T, Bar-Sagi D . (1999). Mol Cell Biol 19: 5892–5901.

  • Katzav S, Cleveland JL, Heslop HE, Pulido D . (1991). Mol Cell Biol 11: 1912–1920.

  • Katzav S, Martin-Zanca D, Barbacid M . (1989). EMBO J 8: 2283–2290.

  • Kuhne MR, Ku G, Weiss A . (2000). J Biol Chem 275: 2185–2190.

  • Lassus P, Roux P, Zugasti O, Philips A, Fort P, Hibner U . (2000). Oncogene 19: 2377–2385.

  • Lavau C, Szilvassy SJ, Slany R, Cleary ML . (1997). EMBO J 16: 4226–4237.

  • Lin R, Cerione RA, Manor D . (1999). J Biol Chem 274: 23633–23641.

  • Lopez-Lago M, Lee H, Cruz C, Movilla N, Bustelo XR . (2000). Mol Cell Biol 20: 1678–1691.

  • Manetz TS, Gonzalez-Espinosa C, Arudchandran R, Xirasagar S, Tybulewicz V, Rivera J . (2001). Mol Cell Biol 21: 3763–3774.

  • Michaelson D, Silletti J, Murphy G, D’Eustachio P, Rush M, Philips MR . (2001). J Cell Biol 152: 111–126.

  • Moll J, Sansig G, Fattori E, van der Putten H . (1991). Oncogene 6: 863–866.

  • Movilla N, Bustelo XR . (1999). Mol Cell Biol 19: 7870–7885.

  • Nakahata T, Ogawa M . (1982). J Cell Physiol 111: 239–246.

  • Nilsson JA, Cleveland JL . (2003). Oncogene 22: 9007–9021.

  • Nishida K, Kaziro Y, Satoh T . (1999). Oncogene 18: 407–415.

  • Schuebel KE, Bustelo XR, Nielsen DA, Song BJ, Barbacid M, Goldman D et al. (1996). Oncogene 13: 363–371.

  • Schuebel KE, Movilla N, Rosa JL, Bustelo XR . (1998). EMBO J 17: 6608–6621.

  • Shirsat NV, Pignolo RJ, Kreider BL, Rovera G . (1990). Oncogene 5: 769–772.

  • Wahlers A, Schwieger M, Li Z, Meier-Tackmann D, Lindemann C, Eckert HG et al. (2001). Gene Therapy 8: 477–486.

  • Walmsley MJ, Ooi SK, Reynolds LF, Smith SH, Ruf S, Mathiot A et al. (2003). Science 302: 459–462.

  • Wang XW . (1999). Anticancer Res 19: 4759–4771.

  • Williams DA, Tao W, Yang FC, Kim C, Gu Y, Mansfield P et al. (2000). Blood 96: 1646–1654.

  • Yang FC, Kapur R, King AJ, Tao W, Kim C, Borneo J et al. (2000). Immunity 12: 557–568.

  • Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ . (1996). Cell 87: 619–628.

  • Zmuidzinas A, Fischer KD, Lira SA, Forrester L, Bryant S, Bernstein A et al. (1995). EMBO J 14: 1–11.

Download references

Acknowledgements

We thank Dr G Bokoch at Scripps Institute for the Rac2-specific antibody and Dr SK Bronson at Penn. State University for the transgenic Bcl-2 mice. We are also grateful to Victoria Summey-Harner and Andrew Lee for bone marrow transplantation technical support. We specially thank Dr D Williams for his helpful discussion and critical comments on the manuscript. This work is supported by NIH R01 GM53943 Grant (YZ) and NIH K01 CA107110 (YG).

Author information

Authors and Affiliations

  1. Division of Experimental Hematology, Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Y Gu, J E Siefring, L Wang, H-D Chae, J R Bailey & Y Zheng

Authors
  1. Y Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J E Siefring
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H-D Chae
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J R Bailey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Gu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gu, Y., Siefring, J., Wang, L. et al. Oncogenic Vav1 induces Rac-dependent apoptosis via inhibition of Bcl-2 family proteins and collaborates with p53 deficiency to promote hematopoietic progenitor cell proliferation. Oncogene 25, 3963–3972 (2006). https://doi.org/10.1038/sj.onc.1209427

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209427

Keywords

Search

Advanced search

Quick links