Oncogenic Vav1 induces Rac-dependent apoptosis via inhibition of Bcl-2 family proteins and collaborates with p53 deficiency to promote hematopoietic progenitor cell proliferation.
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.
Gu
Y
Y
Division of Experimental Hematology, Children's Hospital Research Foundation, University of Cincinnati College of Medicine, OH 45229, USA. yi.gu@cchmc.org
Siefring
J E
JE
Wang
L
L
Chae
H-D
HD
Bailey
J R
JR
Zheng
Y
Y
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D049109:Cell Proliferation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D051567:Proto-Oncogene Proteins c-vav / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D020744:rac GTP-Binding Proteins / Q000502:physiology*
D019253:Proto-Oncogene Proteins c-bcl-2; D051567:Proto-Oncogene Proteins c-vav; D016159:Tumor Suppressor Protein p53; C496619:Vav1 protein, mouse; D020744:rac GTP-Binding Proteins