PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage.
Protein kinase B (PKB/Akt) is ubiquitously expressed in cells. Phosphorylation of its multiple targets in response to various stimuli, including growth factors or cytokines, promotes cell survival and inhibits apoptosis. PKB is upregulated in many different cancers and a significant amount of the enzyme is present in its activated form. Here we show that PKB phosphorylates one of the anti-apoptotic proteins--transcription factor Twist-1 at Ser42. Cells expressing Twist-1 displayed inefficient p53 upregulation in response to DNA damage induced by gamma-irradiation or the genotoxic drug adriamycin. This influenced the activation of p53 target genes such as p21(Waf1) and Bax and led to aberrant cell-cycle regulation and the inhibition of apoptosis. The impaired induction of these p53 effector molecules is likely to be mediated by PKB-dependent phosphorylation of Twist-1 because, unlike the wild-type mutant, the Twist-1 S42A mutant did not confer cell resistance to DNA damage. Moreover, phosphorylation of Twist-1 at Ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of Twist-1 after promotion of survival during carcinogenesis.
Vichalkovski
A
A
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel, Switzerland.
Gresko
E
E
Hess
D
D
Restuccia
D F
DF
Hemmings
B A
BA
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation; D004317:Doxorubicin / Q000633:toxicity; D004789:Enzyme Activation; D005720:Gamma Rays; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012694:Serine; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000737:chemistry* / Q000378:metabolism*
D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D016159:Tumor Suppressor Protein p53; D051879:Twist-Related Protein 1; D012694:Serine; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt