Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25A (Nat Cell Biol, 2010, 12:400-406)

報告日期: 2010/10/15
報告時間: 15:10/16:00
報告學生: 任純儀
講評老師: 洪澤民
附件下載:

Full Text:  http://basicmed.med.ncku.edu.tw/admin/up_img/991015-1.pdf

Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25A

 

Yaron Pereg, Bob Y. Liu, Karen M. O’Rourke, Meredith Sagolla, Anwesha Dey,

Laszlo Komuves, Dorothy M. French and Vishva M. Dixit

 

Nature Cell Biology 2010 Apr; 12(4):400-406

 

Speaker: 任純儀

Commentator: 洪澤民 老師

Time: 2010/10/15 15:10-16:00

Place: Room 602

 

Abstract:

Cdc25A belongs to CDC25 family which is highly conserved phosphatases that activate cyclin-dependent kinase (CDK) to regulate cell cycle progression1. To make sure cell cycle progresses timely, Cdc25A expression must be tightly regulated by ubiquitin-proteasome system. Deregulation of Cdc25A was reported to result in genomic instability2. In line with recent researches, Cdc25A has been reported to be overexpressed in several cancers, such as esophageal cancer, lung cancer and breast cancer. Though Cdc25A overexpression has been found in several cancers, there’s no Cdc25a gene amplification and rearrangement has been reported. These authors thus hypothesized that Cdc25A may be stabilized by deubiquitylating enzyme (DUB). After screening 107 DUBs in 293T cells, they found that Dub3 can specifically bind to Cdc25A and stabilize Cdc25A by removing its polyubiquitin modification. These authors further knockdown Dub3 expression in osteosarcoma U2-OS cells. They found that Cdc25A degradation was increased. And this Cdc25A down-regulation led to Cdk/cyclin activity reduction and cell cycle arrest at G1/S and G2/M phases. When these authors overexpressed Dub3 in U2-OS cells, cells were found to accumulate in S and G2 phases due to the replication stress, and triggered a DNA damage response. Last but not the least, the authors showed that Dub3 has the oncogenic potential. They proved that Dub3 can promote cell anchorage-independent growth when cooperated with H-Ras. Besides, these authors knockdown Dub3 expression and found the growth of breast tumor xenografts in nude mice was decreased. In conclusion, these results pointed that Dub3, as the upstream regulator of Cdc25A, can promote oncogenic transformation and might serve as a promising therapeutic target to treat cancer.

 

References:

1.  Boutros, R., Lobjois, V. and Ducommun, B. CDC25 phosphatases in cancer cells: key players? Good targets? Nature Rev. Cancer 7, 495-507 (2007).

2.  Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864-870 (2005).