Functional interaction between Env oncogene from Jaagsiekte sheep retrovirus and tumor suppressor Sprouty2.
BACKGROUND
Jaagsiekte sheep retrovirus (JSRV) is a type D retrovirus capable of transforming target cells in vitro and in vivo. The Envelope (Env) gene from JSRV and from related retroviruses can induce oncogenic transformation, although the detailed mechanism is yet to be clearly understood. Host cell factors are envisaged to play a critical determining role in the regulation of Env-mediated cell transformation.


RESULTS
JSRV Env-mediated transformation of a lung adenocarcinoma cell line induced rapid proliferation, anchorage-independent growth and tumor formation, but completely abrogated the migration ability. An analysis of the signaling scenario in the transformed cells suggested the involvement of the ERK pathway regulated by Sprouty2 in cell migration, and the PI3K-Akt and STAT3 pathways in proliferation and anchorage-independence. On the other hand, in a normal lung epithelial cell line, Env-mediated transformation only decreased the migration potential while the other functions remained unaltered. We observed that Env induced the expression of a tumor suppressor, Sprouty2, suggesting a correlation between Env-effect and Sprouty2 expression. Overexpression of Sprouty2 per se not only decreased the migratory potential and tumor formation potential of the target cells but also made them resistant to subsequent Env-mediated transformation. On the other hand, over expression of the functional mutants of Sprouty2 had no inhibitory effect, confirming the role of Sprouty2 as a tumor suppressor.


CONCLUSIONS
Our studies demonstrate that Env and Sprouty2 have a functional relationship, probably through shared signaling network. Sprouty2 functions as a tumor suppressor regulating oncogenic transformation of cells, and it therefore has the potential to be exploited as a therapeutic anti-cancer agent.
Chitra
Ebenezer
E
Vaccine R&D Center, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County 350, Taiwan.
Lin
Yi-Wen
YW
Davamani
Fabian
F
Hsiao
Kuang-Nan
KN
Sia
Charles
C
Hsieh
Shih-Yang
SY
Wei
Olivia L
OL
Chen
Jen-Hao
JH
Chow
Yen-Hung
YH
D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002472:Cell Transformation, Viral; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015686:Gene Products, env / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D022141:Jaagsiekte sheep retrovirus / Q000472:pathogenicity*; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping
D015686:Gene Products, env; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; C485561:SPRY2 protein, human