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Fig. 3. Altering Rheb-TOR-S6K signaling can influence the response of adult flies to oxidative stress. Although increasing Rheb-TOR-S6K signaling sensitizes flies to oxidative stress (A), decreasing signaling through this pathway provides resistance to oxidative stress (B). Furthermore, Rheb-TOR signaling requires S6K to confer sensitivity to the whole organism to oxidative stress (C). The mean survival 24 hours after start of treatment with 5% H₂O₂ in 5% sucrose/PBS is 81% for hsGAL4/w flies (control) and 82% for daGAL4/w flies (control), but was only 33% for hs>TOR flies (n=117, P=0.0061) and 5% for da>S6K^STDETE flies (n=117, P=0.0014) (A). The mean survival 36 hours after start of treatment with 5% H₂O₂ in 5% sucrose/PBS is 57% for hs>Tsc1/2 flies (n=129, P=0.0169), 62% for da>Tsc2 flies (n=126, P=0.0059), 41% for da>TOR^FRB flies (n=106, P=0.3194), 97% for hs>S6K^KQ flies (n=117, P=0.0030) and 84% for da>S6K^KQ flies (n=117, P=0.0401), it was however, only 10% for hsGAL4/w flies (control) and 14% for daGAL4/w flies (control) (B). Overexpression of a dominant-negative form of TOR^FRB can partially rescue the sensitivity of flies overexpressing Rheb with hs-GAL4 (hs>Rheb) (C). Furthermore overexpression of a dominant-negative form of S6K^KQ can fully rescue the sensitivity of flies overexpressing Rheb (P=0.1835, NS) (C). The mean survival after 6 days is 94% for hsGAL4/w flies (control), 17% for hs>Rheb flies, 40% for hs>Rheb; TOR^FRB flies and 75% for hs>Rheb; S6K^KQ flies (C). Error bars represent the s.d. Statistical comparison (T-test): all P values are based on comparison of the overexpressor with controls (hsGAL4/w and daGAL4/w). (D) Scheme for the involvement of TSC-Rheb-TOR-S6K signaling in the stress response.

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