p53 hot-spot mutants increase tumor vascularization via ROS-mediated activation of the HIF1/VEGF-A pathway
被引:73
作者:
Khromova, N. V.
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Blokhin Mem Russian Canc, Res Ctr, Moscow 115478, RussiaBlokhin Mem Russian Canc, Res Ctr, Moscow 115478, Russia
Khromova, N. V.
[1
]
Kopnin, P. B.
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机构:
VA Engelhardt Mol Biol Inst, Moscow 119991, Russia
Univ Oslo, Ctr Med Studies Russia, Moscow 119334, RussiaBlokhin Mem Russian Canc, Res Ctr, Moscow 115478, Russia
Kopnin, P. B.
[2
,3
]
Stepanova, E. V.
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Blokhin Mem Russian Canc, Res Ctr, Moscow 115478, RussiaBlokhin Mem Russian Canc, Res Ctr, Moscow 115478, Russia
Stepanova, E. V.
[1
]
Agapova, L. S.
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Blokhin Mem Russian Canc, Res Ctr, Moscow 115478, RussiaBlokhin Mem Russian Canc, Res Ctr, Moscow 115478, Russia
Agapova, L. S.
[1
]
Kopnin, B. P.
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Blokhin Mem Russian Canc, Res Ctr, Moscow 115478, RussiaBlokhin Mem Russian Canc, Res Ctr, Moscow 115478, Russia
Kopnin, B. P.
[1
]
机构:
[1] Blokhin Mem Russian Canc, Res Ctr, Moscow 115478, Russia
[2] VA Engelhardt Mol Biol Inst, Moscow 119991, Russia
[3] Univ Oslo, Ctr Med Studies Russia, Moscow 119334, Russia
The function of p53 tumor suppressor is often altered in various human tumors predominantly through missense-mutations resulting in accumulation of mutant proteins. we revealed that expression of p53 proteins with amino-acid substitutions at codons 175 (R175H), 248 (R248W), and 273 (R273H), representing the hot-spots of mutations in various human tumors, increased the number of vessels in HCT116 human colon carcinoma xenografts and, as a result, accelerated their growth. Stimulation of tumor angiogenesis was connected with about 2-fold increase in intracellular level of reactive oxygen species (ROS). Antioxidant N-acetyl-L-aspartate (NAC) decreased vessels number in tumors formed by cells with inactivated p53 and inhibited their growth. Effect of ROS on angiogenesis in tumors expressing hot-spot p53 mutants was correlated with their ability to increase a content of HIF1 transcriptional factor responsible for up-regulation of VEGF-A mRNAs. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
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Beth Israel Deaconess Med Ctr, Harvard Med Sch, Dept Med, Div Mol & Vasc Med, Boston, MA 02215 USABeth Israel Deaconess Med Ctr, Harvard Med Sch, Dept Med, Div Mol & Vasc Med, Boston, MA 02215 USA
Abid, Md. Ruhul
;
Spokes, Katherine C.
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机构:Beth Israel Deaconess Med Ctr, Harvard Med Sch, Dept Med, Div Mol & Vasc Med, Boston, MA 02215 USA
Spokes, Katherine C.
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Shih, Shou-Ching
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机构:Beth Israel Deaconess Med Ctr, Harvard Med Sch, Dept Med, Div Mol & Vasc Med, Boston, MA 02215 USA
Shih, Shou-Ching
;
Aird, William C.
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机构:Beth Israel Deaconess Med Ctr, Harvard Med Sch, Dept Med, Div Mol & Vasc Med, Boston, MA 02215 USA
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Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan
Futamura, Manabu
;
Kamino, Hiroki
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Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan
Kamino, Hiroki
;
Miyamoto, Yuji
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Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan
Miyamoto, Yuji
;
Kitamura, Noriaki
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Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan
Kitamura, Noriaki
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Nakamura, Yasuyuki
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Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan
Nakamura, Yasuyuki
;
Ohnishi, Shiho
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Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan
Ohnishi, Shiho
;
Masuda, Yoshiko
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Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan
Masuda, Yoshiko
;
Arakawa, Hirofumi
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Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan
机构:
Beth Israel Deaconess Med Ctr, Harvard Med Sch, Dept Med, Div Mol & Vasc Med, Boston, MA 02215 USABeth Israel Deaconess Med Ctr, Harvard Med Sch, Dept Med, Div Mol & Vasc Med, Boston, MA 02215 USA
Abid, Md. Ruhul
;
Spokes, Katherine C.
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机构:Beth Israel Deaconess Med Ctr, Harvard Med Sch, Dept Med, Div Mol & Vasc Med, Boston, MA 02215 USA
Spokes, Katherine C.
;
Shih, Shou-Ching
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机构:Beth Israel Deaconess Med Ctr, Harvard Med Sch, Dept Med, Div Mol & Vasc Med, Boston, MA 02215 USA
Shih, Shou-Ching
;
Aird, William C.
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机构:Beth Israel Deaconess Med Ctr, Harvard Med Sch, Dept Med, Div Mol & Vasc Med, Boston, MA 02215 USA
机构:
Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan
Futamura, Manabu
;
Kamino, Hiroki
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机构:
Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan
Kamino, Hiroki
;
Miyamoto, Yuji
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机构:
Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan
Miyamoto, Yuji
;
Kitamura, Noriaki
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机构:
Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan
Kitamura, Noriaki
;
Nakamura, Yasuyuki
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Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan
Nakamura, Yasuyuki
;
Ohnishi, Shiho
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Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan
Ohnishi, Shiho
;
Masuda, Yoshiko
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Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan
Masuda, Yoshiko
;
Arakawa, Hirofumi
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Natl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, JapanNatl Canc Ctr, Res Inst, Canc Med & Biophys Div, Chuo Ku, Tokyo 1040045, Japan