p21-activated protein kinase gamma-PAK is activated by ionizing radiation and other DNA-damaging agents. Similarities and differences to alpha-PAK.
The p21-activated protein kinase gamma-PAK is activated 2-5-fold in response to ionizing radiation (IR) in 3T3-L1 fibroblasts and U937 leukemia cells. gamma-PAK is activated in a dose- and time-dependent manner. Doses from 1 to 100 Gy result in significant stimulation of activity at 30 min, whereas maximal stimulation is observed at 120 min after irradiation. UV (80 J/m(2)) and the DNA-damaging drugs cytosine beta-D-arabinofuranoside (AraC) and cis-platinum(II)diammine dichloride (cisplatin) also induce gamma-PAK activation. The activation of gamma-PAK in response to IR or AraC is dependent on tyrosine kinase and phosphoinositide 3-kinase activity, as demonstrated by use of the inhibitors genistein and wortmannin; in contrast activation of gamma-PAK by cisplatin and UV is not affected significantly by these inhibitors, suggesting that gamma-PAK can be activated by more than one pathway in response to different types of DNA damage. In contrast to gamma-PAK, alpha-PAK and JNK are activated only by cisplatin and UV in 3T3-L1 cells, suggesting differential regulation of the protein kinases. This is the first time that members of the Ste20/PAK family of protein kinases have been shown to be involved in the cellular response to IR and other DNA-damaging agents.
Roig
J
J
Department of Biochemistry, University of California, Riverside, California 92521, USA.
Traugh
J A
JA
D016475:3T3 Cells; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002945:Cisplatin / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D004249:DNA Damage; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation; D005720:Gamma Rays; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009153:Mutagens / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000528:radiation effects*; D011839:Radiation, Ionizing; D020298:U937 Cells; D014466:Ultraviolet Rays; D000077191:Wortmannin; D054462:p21-Activated Kinases
D000730:Androstadienes; D009153:Mutagens; D003561:Cytarabine; D019833:Genistein; C515907:PAK2 protein, human; C515909:Pak2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D002945:Cisplatin; D000077191:Wortmannin