Team:SYSU-China/Project/Design

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ipsc

UPDATE 09/18/2013

suicide gene?

Why suicide gene?

In our project, we try to build a circuit that can prevent the iPSC-differentiated tissues from tumor formation. Instead of using some medicines to kill them, like the traditional gene therapies did, what we want to achieve here is to make the tumor cells kill themselves, in other word, automatically commit suicide. So we decided to use an exogenous suicide gene.

The ideal suicide genes that fit our design here will be genes that can successfully induce apoptosis in cells and do not introduce any harmful effect to normal tissues. However, many apoptosis pathways are reported to be blocked in tumor cells. From recent reports and papers, we found out that there have been many genes reported to have important roles in mammalian cell apoptosis. After a long time comparison and consideration, our final candidates of suicide gene are listed below:

- hBax & hBax mutant

- delta TK

- caspase3

- rip1

- rip3

- apoptin

The introduction of each genes about its suicide mechanisms and the reasons why we choose them are as follows:

References

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[3]Amotz Nechushtan et al, Conformation of the Bax C-terminus regulates subcellular location and cell death, The EMBO Journal Vol.18 No.9 pp.2330–2341, 1999.

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[9]N Festjens, T Vanden Berghe et al,RIP1, a kinase on the crossroads of a cell's decision to live or die, Cell Death and Differentiation (2007) 14, 400–410

[10]RIP3, an Energy Metabolism Regulator That Switches TNF-Induced Cell Death from Apoptosis to Necrosis

[11]Nils Holler et al, Fas triggers an alternative, caspase-8−independent cell death pathway using the kinase RIP as effector molecule, Nature Immunology 1, 489 - 495 (2000)

[12] Liming Sun et al,Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase,Cell,2012, 148, 213–227

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[15]Xiaoqing Sun et al ,RIP3, a Novel Apoptosis-inducing Kinase, THE JOURNAL OF BIOLOGICAL CHEMISTRY, Vol. 274, No. 24, Issue of June 11, pp. 16871–16875, 1999

[16]Shi-Mei Zhuang et al, Apoptin, a Protein Derived from Chicken Anemia Virus, Induces p53-independent Apoptosis in Human Osteosarcoma Cells, Cancer Res 1995;55:486-489,

[17]Claude Backendorf et al, Apoptin: Therapeutic Potential of an Early Sensor of Carcinogenic Transformation, Annu. Rev. Pharmacol. Toxicol. 2008. 48:143–69

[18]Xiao Li et al, Antitumor effects of a recombinant fowlpox virus expressing Apoptin in vivo and in vitro, Int. J. Cancer: 119, 2948–2957 (2006)

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[20]Lars Guelen et al,TAT-apoptin is efficiently delivered and induces apoptosis in cancer cells, Oncogene (2004) 23, 1153–1165

[21]Su-Xia Han et al,Secretory Transactivating Transcription-apoptin fusion protein induces apoptosis in hepatocellular carcinoma HepG2 cells, World J Gastroenterol ,2008, 14(23): 3642-3649

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Sun Yat-Sen University, Guangzhou, China

Address: 135# Xingang Rd.(W.), Haizhu Guangzhou, P.R.China