A Rationally Designed Peptide " Super

advertisement
A Peptide Mimicking VGLL4 Function Acts
as a YAP Antagonist Therapy against
Gastric Cancer
Feng Junnan
Cancer Cell 25, 166–180, February 10, 2014
Introduction
Experimental design
VGLL4 is a potential
tumor suppressor
Function Study
How does VGLL4 function?
Mechanism Study
Key residues for
VGLL4-TEAD4 complex
formation?
A Rationally Designed Peptide
“Super-TDU”
2015/4/7
Structural Study
Clinical Study
Result 1:
2015/4/7
VGLL4 Is a Potential Tumor Suppressor
in Human Gastric Cancer
Result 2:
2015/4/7
VGLL4 Suppresses GC Growth in Vitro by
Targeting YAP-TEADs
Result 3:
2015/4/7
VGLL4 Functions through Competing with
YAP for TEAD4 Binding
Result 4:
2015/4/7
TDU Domains Alone Are Sufficient for VGLL4
Function of Inhibiting YAP
Structural Study
Result 5:
2015/4/7
A Rationally Designed Peptide " Super-TDU "
Potently Inhibits GC Growth
1、Inhibits GC Growth
2、Pharmacological Evaluation of the Super-TDU
3、Inhibits Tumor Growth of Human Primary GC
4、 Inhibits GC Tumor Growth in the H. pylori-Infected Mouse Model
summary
Super--TDU
cancer cell
overactive YAP
Gains
• Important signal pathway -- Hippo
• Novel therapy against cancer -- Physical antagonist
• Simple technologies , rigorous design.
References
• Avruch, J., Zhou, D., and Bardeesy, N. (2012). YAP oncogene overexpression
supercharges colon cancer proliferation. Cell Cycle11, 1090–1096.
• Azzolin, L., Zanconato, F., Bresolin, S., Forcato, M., Basso, G., Bicciato, S.,Cordenonsi,
M., and Piccolo, S. (2012). Role of TAZ as mediator of Wnt signaling. Cell151, 1443–
1456.
• Barry, E.R., Morikawa, T., Butler, B.L., Shrestha, K., de la Rosa, R., Yan, K.S.,Fuchs, .S.,
Magness, S.T., Smits, R., Ogino, S., et al. (2013). Restriction of intestinal stem cell
expansion and the regenerative response by YAP. Nature 493, 106–110.
• Cai, J., Zhang, N., Zheng, Y., de Wilde, R.F., Maitra, A., and Pan, D. (2010). The Hippo
ignaling pathway restricts the oncogenic potential of an intestinal regeneration
program. Genes Dev.24, 2383–2388.
• Chan, S.W., Lim, C.J., Chen, L., Chong, Y.F., Huang, C., Song, H., and Hong,W. (2011).
The Hippo pathway in biological control and cancer development.J. Cell. Physiol.226,
928–939.
Download