PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms

Freeman, Daniel J.; Li, Andrew G.; Wei, Gang; Li, Heng-Hong; Kertesz, Nathalie; Lesche, Ralf; Whale, Andrew; Martinez-Diaz, Hilda; Rozengurt, Nora; Cardiff, Robert D.; Li, Xuan; Wu, Hong

doi:10.1016/s1535-6108(03)00021-7

Cited by 454 publications

(426 citation statements)

References 55 publications

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“…19,20 A functional p53 binding site has been identified within the PTEN promoter region, suggesting that p53 is able to regulate PTEN expression.…”

Section: Discussionmentioning

confidence: 99%

“…17,18 Recently, important interactions between the PI3K-AKT and p53 signaling pathways have been described. [19][20][21] Studies on cell line suggest that activation of the PI3K pathway through PTEN or PIK3CA mutations causes activation of p53. It has been reported that activation of the PI3K-AKT pathway together with p53 inactivation results in malignant transformation.…”

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confidence: 99%

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Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

et al. 2009

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The status of p53 and the phosphatidylinositol 3-kinase-AKT (PI3K-AKT) signaling pathway was investigated in 132 endometrial carcinomas, including endometrioid endometrial carcinomas, non-endometrioid endometrial carcinomas, and mixed endometrioid adenocarcinomas-non-endometrioid adenocarcinomas. Results were compared with the clinicopathologic parameters associated with prognosis, patients' follow-up, and other genetic alterations found frequently in these tumors. Molecular genetic differences between low-grade and high-grade endometrioid adenocarcinomas were encountered; ie, PIK3CA mutations were detected in 26 and 34% of cases, respectively. We found p53 alterations in only 17% of high-grade endometrioid adenocarcinomas. In contrast, non-endometrioid adenocarcinomas had a higher frequency of p53 alterations (54%), PIK3CA mRNA overexpression (45%), and exon 20 PIK3CA mutations (21%). In the mixed endometrioid adenocarcinomas-non-endometrioid adenocarcinomas, the most frequent alterations were p53 (50%) and PIK3CA (44%) mutations, followed by PTEN mutations (38%). In some cases, p53 and PIK3CA alterations coexisted, but they rarely coexisted with the PTEN mutations. Our findings suggest that the PIK3CA mutations are frequent events in endometrial carcinomas of any histological type. However, location of the PIK3CA mutations, either in exon 9 or exon 20, varies significantly according to the histologic grade and type of carcinoma. Carcinomas with exon 20 PIK3CA mutations or PIK3CA mRNA overexpression were often high-grade carcinomas associated with myometrial invasion; in contrast, tumors that carried exon 9 mutations were more likely to be low-grade carcinomas. The Kaplan-Meier analysis suggested that p53 alterations (strong immunoexpression or mutations) conferred a worse prognosis (P ¼ 0.000). Although alterations in the PI3K-AKT signaling pathway alone did not influence overall survival, patients with deregulated PI3K-AKT pathway (PIK3CA and/or PTEN alterations) and p53 alterations had shorter survival (P ¼ 0.000) than patients with only p53 alterations. Such a relationship was lost when we considered exon 9 PIK3CA mutations. Our results contribute to further characterize the molecular genetic model for endometrial carcinogenesis.

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“…19,20 A functional p53 binding site has been identified within the PTEN promoter region, suggesting that p53 is able to regulate PTEN expression.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

et al. 2009

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“…Given the ability of PTEN to indirectly stabilize p53 protein through antagonizing the Akt-MDM2 pathway (4,10,26) or by directly increasing p53 acetylation (27), decreased p53 activity in PTEN-deficient tumor cells should be expected and would explain the comparably preferential activity of caffeine in radiosensitizing p53-deficient (Table 1A; refs. 23,24) and PTEN-deficient tumor cells (Table 1A; Fig.…”

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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“…Thus, whereas p53 enhances PTEN transcription, PTEN physically stabilizes the p53 protein by direct interaction, in addition to transcriptional downregulation of MDM2 through the P1 promoter and inhibition of Akt-dependent MDM2 phosphorylations. 93,[169][170][171][172][173] DNA damage, on the other hand, may lead to p53-dependent degradation of Akt. 174 Although somatic mutations in PTEN occurs at high frequency in some cancers, like endometrial carcinomas, they are rare in breast cancer.…”

Section: Activating Mutations In the Pten/pi3k/mtor Pathway As A Causmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms

Cited by 454 publications

References 55 publications

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

Concomitant PI3K–AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis

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

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

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