PH Domain-Only Protein PHLDA3 Is a p53-Regulated Repressor of Akt

Kawase, Tatsuya; Ohki, Rieko; Shibata, Tatsuhiro; Tsutsumi, Sadami; Kamimura, Naoko; Inazawa, Johji; Ohta, Tsutomu; Ichikawa, Hitoshi; Aburatani, Hiroyuki; Tashiro, Fumio; Taya, Yoichi

doi:10.1016/j.cell.2008.12.002

Cited by 212 publications

(243 citation statements)

References 36 publications

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“…Based on our results, we hypothesize that the regulation of Akt activation by CABYR-a/b is likely posttranslational, and this hypothesis is also supported by observations that gene amplification (data not shown) and total Akt protein levels do not change in CABYR-a/b-silenced cells compared with mock controls. One possible mechanism may be that CABYR-a/b indirectly regulates Akt dephosphorylation by modulating proteins that terminate Akt signaling through the dephosphorylation and inactivation of Akt, such as PHLPP (25), CTMP (26), PHLDA3 (27), and FKBP51 (28). Conversely, CABYR-a/b may also influence the activation of Akt directly or indirectly.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of CABYR-a/b Increases Chemosensitivity of Human Non–Small Cell Lung Cancer Cells through Inactivation of Akt

Qian

Wang

et al. 2014

Molecular Cancer Research

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CABYR is a calcium-binding tyrosine phosphorylation-regulated protein that was identified as a novel cancer testis antigen in lung cancer in our previous study. However, the role of CABYR as a driver of disease progression or as a chemosensitizer is poorly understood. This study sought to investigate the relationship between the expression levels of CABYR-a/b, which are the two predominant isoforms of the five isoform proteins encoded by CABYR, and chemosensitivity in non-small cell lung cancer cells. We found that the short hairpin RNA-mediated knockdown of CABYR-a/b significantly inhibited the proliferation of NCI-H460 and A549 cells and resulted in the attenuation of Akt phosphorylation, which is constitutively active in lung cancer cells. The silencing of CABYR-a/b expression notably impacted the downstream components of the Akt pathways: decreasing the phospho-GSK-3b (Ser9) levels and increasing the expression of the p53 and p27 proteins. Furthermore, CABYR-a/b knockdown led to a significant increase in chemosensitivity in response to chemotherapeutic drugs and drug-induced apoptosis, both in vitro and in vivo. Conversely, the transient transfection of CABYR-a/b-depleted cells with constitutively active Akt partially restored the resistance to cisplatin and paclitaxel and significantly decreased the activation of GSK-3b and cleaved PARP. Taken together, our results suggest that the inhibition of CABYR-a/b is a novel method to improve the apoptotic response and chemosensitivity in lung cancer and that this cancer testis antigen is an attractive target for lung cancer drug development.

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Section: Discussionmentioning

confidence: 99%

Knockdown of CABYR-a/b Increases Chemosensitivity of Human Non–Small Cell Lung Cancer Cells through Inactivation of Akt

Qian

Wang

et al. 2014

Molecular Cancer Research

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“…However, a role of PTEN as mediator of such p53-dependent inhibition of Akt phosphorylation can be excluded in our model of PTEN-deficient glioma cells. Whether or not PHLDA3, a further p53-regulated repressor of Akt identified very recently (32), contributes to the suppression of Akt phosphorylation in PTEN-deficient glioma cells irradiated in the presence of caffeine remains to be determined in future studies.…”

Section: Discussionmentioning

confidence: 99%

Caffeine Confers Radiosensitization of PTEN-Deficient Malignant Glioma Cells by Enhancing Ionizing Radiation–Induced G1 Arrest and Negatively Regulating Akt Phosphorylation

Sinn

Tallen²,

Schroeder³

et al. 2010

Molecular Cancer Therapeutics

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PTEN mutations are frequently found in malignant glioma and can result in activated phosphatidylinositol-3-kinase/Akt survival signaling associated with resistance to radiotherapy. Strategies to interfere with aberrant PI3K/Akt activity are therefore being developed to improve the therapeutic efficacy of radiotherapy in patients with malignant glioma. The methylxanthine caffeine has been described as a PI3K inhibitor and is also known to sensitize cells to ionizing radiation. However, a direct association between these two caffeinemediated effects has not been reported yet. Therefore, we asked whether caffeine or its derivative pentoxifylline differentially affect the radiosensitivity of malignant gliomas with different PTEN status. As models, we used the radiosensitive EA14 malignant glioma cell line containing wild-type PTEN and the radioresistant U87MG malignant glioma cell line harboring mutant PTEN. Our study revealed that caffeine and pentoxifylline radiosensitized PTEN-deficient but not PTEN-proficient glioma cells. Radiosensitization of PTENdeficient U87MG cells by caffeine was significantly correlated with the activation of the G 1 DNA damage checkpoint that occurred independently of de novo synthesis of p53 and p21. The p53 independency was also confirmed by a significant caffeine-mediated radiosensitization of the glioma cell lines T98G and U373MG that are deficient for both PTEN and p53. Furthermore, caffeine-mediated radiosensitization was associated with the inhibition of Akt hyperphosphorylation in PTEN-deficient cells to a level comparable with PTEN-proficient cells. Our data suggest that the methylxanthine caffeine or its derivative pentoxifylline are promising candidate drugs for the radiosensitization of glioma cells particularly with PTEN mutations. Mol Cancer Ther; 9(2); 480-8. ©2010 AACR.

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“…Although studies on a closely related gene, Phlda3, suggest a role for these PH domain-only proteins in inhibiting Akt-regulated processes (Kawase et al 2009), this has not been formally demonstrated for Phlda2. Expression of Phlda2 in the placenta is first detected in the ectoplacental cone following implantation, becoming restricted to the syncytiotrophoblast of the labyrinth layer by E10.5 (Frank et al 1999).…”

Section: D13mentioning

confidence: 99%

Imprinted genes in mouse placental development and the regulation of fetal energy stores

2013

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Imprinted genes, which are preferentially expressed from one or other parental chromosome as a consequence of epigenetic events in the germline, are known to functionally converge on biological processes that enable in utero development in mammals. Over 100 imprinted genes have been identified in the mouse, the majority of which are both expressed and imprinted in the placenta. The purpose of this review is to provide a summary of the current knowledge regarding imprinted gene function in the mouse placenta. Few imprinted genes have been assessed with respect to their dosage-related action in the placenta. Nonetheless, current data indicate that imprinted genes converge on two key functions of the placenta, nutrient transport and placental signalling. Murine studies may provide a greater understanding of certain human pathologies, including low birth weight and the programming of metabolic diseases in the adult, and complications of pregnancy, such as pre-eclampsia and gestational diabetes, resulting from fetuses carrying abnormal imprints.Reproduction (2013) 145 R117-R137

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PH Domain-Only Protein PHLDA3 Is a p53-Regulated Repressor of Akt

Cited by 212 publications

References 36 publications

Knockdown of CABYR-a/b Increases Chemosensitivity of Human Non–Small Cell Lung Cancer Cells through Inactivation of Akt

Knockdown of CABYR-a/b Increases Chemosensitivity of Human Non–Small Cell Lung Cancer Cells through Inactivation of Akt

Caffeine Confers Radiosensitization of PTEN-Deficient Malignant Glioma Cells by Enhancing Ionizing Radiation–Induced G1 Arrest and Negatively Regulating Akt Phosphorylation

Imprinted genes in mouse placental development and the regulation of fetal energy stores

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