PH Domain-Only Protein PHLDA3 Is a p53-Regulated Repressor of Akt
| Autor: | Fumio Tashiro, Shuichi Tsutsumi, Naoko Kamimura, Tatsuhiro Shibata, Tsutomu Ohta, Yoichi Taya, Hiroyuki Aburatani, Tatsuya Kawase, Hitoshi Ichikawa, Johji Inazawa, Rieko Ohki |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Lung Neoplasms
HUMDISEASE Repressor Apoptosis Biology medicine.disease_cause General Biochemistry Genetics and Molecular Biology Mice Phosphatidylinositol Phosphates Cell Line Tumor medicine Animals Humans Phosphorylation Protein kinase B PI3K/AKT/mTOR pathway Mice Knockout Biochemistry Genetics and Molecular Biology(all) Cell growth Cell Membrane Nuclear Proteins Protein Structure Tertiary Cell biology Oncogene Protein v-akt Pleckstrin homology domain SIGNALING Cancer research Tumor Suppressor Protein p53 Signal transduction Carcinogenesis Signal Transduction |
| Zdroj: | Cell. 136:535-550 |
| ISSN: | 0092-8674 |
| Popis: | Summaryp53 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|