Akt regulates G2/M checkpoint of the cell cycle

Akt has been shown to be frequently hyperactivated in many human cancers and has been shown to play an important role in tumorigenesis. An important mechanism by which Akt can promote tumorigenesis is the abrogation of the cell cycle G2/M checkpoint in the presence of DNA damage.;We found that activated Akt can reduce Chk1 activity. Activated Akt recapitulated the combinatory effect of Chk1 knockdown and Bcl2 (an antiapoptotic protein) overexpression. While Akt could directly phosphorylate Chk1 on Serine 280, this phosphorylation did not interfere with Chk1 activation. In terms of stability, we showed that Chk1 stability was unaffected by Akt overexpression.;We also studied the influence of Akt on the mediators of Chk1 activation, BRCA1 and claspin. Activated Akt resulted in almost complete loss of G2/M checkpoint just like knockdown of BRCA1 did. Overexpression of BRCA1 led to a G2/M arrest, which was prevented by introducing activated Akt. BRCA1 stability was unaffected by Akt activation, but it lost ability to translocate to DNA damage foci. In terms of claspin, we found that activated Akt led to a decrease in claspin protein levels. Claspin protein stability was reduced upon DNA damage, due to proteosomal degradation of claspin.