PH domain-only protein PHLDA3 is a p53-regulated repressor of Akt.
p53 And Akt are critical players regulating tumorigenesis with opposite effects: whereas p53 transactivates target genes to exert its function as a tumor suppressor, Akt phosphorylates its substrates and transduces downstream survival signals. In addition, p53 and Akt negatively regulate each other to balance survival and death signals within a cell. We now identify PHLDA3 as a p53 target gene that encodes a PH domain-only protein. We find that PHLDA3 competes with the PH domain of Akt for binding of membrane lipids, thereby inhibiting Akt translocation to the cellular membrane and activation. Ablation of endogenous PHLDA3 results in enhanced Akt activity and decrease of p53-dependent apoptosis. We also demonstrate the suppression of anchorage-independent cell growth by PHLDA3. Loss of the PHLDA3 genomic locus was frequently observed in primary lung cancers, suggesting a role of PHLDA3 in tumor suppression. Our results reveal a new mode of coordination between the p53 and Akt pathways.
Kawase
Tatsuya
T
Radiobiology Division, National Cancer Center Research Institute, Tokyo, Japan.
Ohki
Rieko
R
Shibata
Tatsuhiro
T
Tsutsumi
Shuichi
S
Kamimura
Naoko
N
Inazawa
Johji
J
Ohta
Tsutomu
T
Ichikawa
Hitoshi
H
Aburatani
Hiroyuki
H
Tashiro
Fumio
F
Taya
Yoichi
Y
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D009687:Nuclear Proteins; D018129:Phosphatidylinositol Phosphates; C109277:TSSC3 protein; D016159:Tumor Suppressor Protein p53; D051058:Oncogene Protein v-akt