PKBa/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival (Mol Cell, 2008, 30:203-213)

報告日期: 2008/10/24
報告時間: 17:10/18:00
報告學生: 梁鎮顯
講評老師: 賴明德
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/971024-3.pdf

PKBa/Akt1 Acts Downstream of DNA-PK

in the DNA Double-Strand Break

Response and Promotes Survival

Molecular Cell 30: 203–213, 2008

 

Speaker:梁鎮顯

Commentator:賴明德老師

Date2008/10/24

Room602

 

Abstract

      Serine/threonine protein kinase B (PKB/Akt) is a multifunctional protein which is involve in various cellular processes such as glucose uptake, cell-cycle progression, apoptosis and transcriptional regulation. Several components of the PI3K-PKB pathway have been found were phosphorylated in the DNA damage response. But how to activate PKB following DNA damage remains to be elucidated. Authors used NU7026 [DNA dependent protein kinase (DNA-PK) inhibitor], DNA-PK siRNA to treat cells and 3-phosphoinositide-dependent kinase 1 (PDK1) deficient ES cells to demonstrate that PKB activation following DNA damage requires DNA-PK and PDK1. Immunofluorescence staining for Ser 437-P of PKB and DNA-PKcs also demonstrates that PKB and DNA-PKcs colocalized in the nucleus of g-irradiated cells adjacent to DNA double-strand breaks. Cells lacking PKBa reveal aberrant DNA damage-induced transcriptional, including transcriptional misregulation of p21. PKBa knockout mice also show that p21 expression level was decreased following g-IR and increased DNA damage-induced apoptosis. Above these results, PKB seems to provide a prosurivival signal for the cell by affecting DNA damage-induced transcription, such as p21 transcriptional regulation.  

 

Reference

1. Dummler, B., and Hemmings, B.A. Physiological roles of PKB/Akt isoforms in development and disease. Biochem. Soc. Trans. 35, 231–235 (2007).

2. Leahy, J.J., Golding, B.T., Griffin, R.J., Hardcastle, I.R., Richardson, C., Rigor-eau, L., and Smith, G.C. Identification of a highly potent and selectiveDNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening ofchromenone libraries. Bioorg. Med. Chem. Lett. 14, 6083–6087 (2004).