Lack of PTEN sequesters CHK1 and initiates genetic instability.
Pten-/- cells display a partially defective checkpoint in response to ionizing radiation (IR). The checkpoint defect was traced to the ability of AKT to phosphorylate CHK1 at serine 280, since a nonphosphorylated mutant of CHK1 (S280A) complemented the checkpoint defect and restored CDC25A degradation. CHK1 phosphorylation at serine 280 led to covalent binding of 1 to 2 molecules of ubiquitin and cytoplasmic CHK1 localization. Primary breast carcinomas lacking PTEN expression and having elevated AKT phosphorylation had increased cytoplasmic CHK1 and displayed aneuploidy (p <0.005). We conclude that loss of PTEN and subsequent activation of AKT impair CHK1 through phosphorylation, ubiquitination, and reduced nuclear localization to promote genomic instability in tumor cells.
Puc
Janusz
J
Institute for Cancer Genetics, Columbia University, New York, New York 10032, USA.
Keniry
Megan
M
Li
Hong Shen
HS
Pandita
Tej K
TK
Choudhury
Atish D
AD
Memeo
Lorenzo
L
Mansukhani
Mahesh
M
Murty
Vundavalli V V S
VV
Gaciong
Zbigniew
Z
Meek
Sarah E M
SE
Piwnica-Worms
Helen
H
Hibshoosh
Hanina
H
Parsons
Ramon
R
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D004622:Embryo, Mammalian / Q000166:cytology; D016195:G2 Phase; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics* / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011839:Radiation, Ionizing; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism
D006133:Growth Substances; D011518:Proto-Oncogene Proteins; D025801:Ubiquitin; D012694:Serine; D011494:Protein Kinases; C494918:AKT1 protein, human; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases