p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas

Singh, Bhuvanesh; Reddy, Pabbathi G.; Goberdhan, Andy; Walsh, Christine; Dao, Su; Ngai, Ivan; Chou, Ting‐Chao; O-charoenrat, Pornchai; Levine, Arnold J.; Rao, Pulivarthi H.; Stoffel, Archontoula

doi:10.1101/gad.973602

Cited by 191 publications

(170 citation statements)

References 26 publications

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“…However, there are conflicting data about the correlation of PIK3CA mutation and p53 mutations in cancer. Singh et al (2002) reported that PIK3CA and p53 mutations were mutually exclusive, while Maruyama et al (2007) could not find that associations. In our study, a trend was seen towards mutual exclusivity between PIK3CA mutations and p53 mutations (P ¼ 0.0687).…”

Section: Discussionmentioning

confidence: 97%

“…Then we were interested in studying the relationship between PI3K/AKT pathway and p53 (tumor suppressor gene) since interactions between the p53 and PI3K/ AKT pathways play a significant role in the determination of cell death/survival. Interrelation between these pathways occurs through the transcriptional regulation of PTEN by p53, which is required for p53-mediated apoptosis (Singh et al, 2002;Maruyama et al, 2007). However, there are conflicting data about the correlation of PIK3CA mutation and p53 mutations in cancer.…”

Section: Discussionmentioning

confidence: 99%

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Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

Abubaker¹,

Bavi²,

Al-harbi³

et al. 2008

Oncogene

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Activation of the phosphatidylinositol 3 0 -kinase (PI3K)/ AKT pathway results in an increase in cell proliferation and survival. Somatic mutations within the PI3K catalytic subunit, PIK3CA are common cause of increasing PI3K activity and are believed to be oncogenic in many cancer types. Few reports addressed the association between PIK3CA mutations and tumor progression specifically in microsatellite instable (MSI) colorectal cancer (CRC). In the present study, we have evaluated PIK3CA mutational status in a series of 410 Middle Eastern CRC and 13 colon cell lines to study the prevalence of PIK3CA mutations in MSI cases, PTEN expression in CRC and possibility of therapeutic targeting of this set of patients. PIK3CA mutations were found in four of the cell lines tested and 51 colorectal carcinomas (12.2%). Three of these four mutated cell lines were MSI. PTEN was inactivated in 66.1% of the CRC. Furthermore, we observed a strong association between PIK3CA mutations and MSI status (P ¼ 0.0046) while PTEN loss was more frequent in microsatellite stable (MSS) CRC (P ¼ 0.043). A high prevalence of genetic alterations in PI3K/AKT pathway in Saudi cohort of CRC, predominance of PIK3CA mutations in the MSI subgroup and their possible involvement in development/progression of this subset of CRC are some of the significant findings of our study.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

Abubaker¹,

Bavi²,

Al-harbi³

et al. 2008

Oncogene

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“…11 In addition, recent study showed that induction of P53 resulted in decreased in phosphorylated AKT activity in cell line, which did not express PTEN protein, thus highlighting that p53 was involved in regulation of survival PI3K/AKT pathway in epithelial tumors, and independently of PTEN expression. 12 It was reported that activation of p53-dependent downstream targets BAX with concomitant increase of MAPKinase (MAPK) pathways leading to apoptosis. 13 Altogether, these data indicated that the relationship between P53, PI3K/AKT and MAPK signaling pathways offers novel valuable insights into the resistance to targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

P53 and PTEN expression contribute to the inhibition of EGFR downstream signaling pathway by cetuximab

Bouali

Ramacci

et al. 2009

Cancer Gene Ther

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Cetuximab (Erbitux) is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody whose activity is related to the inhibition of EGFR downstream signaling pathways. P53 and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) have been reported to control the functionality of PI3K/AKT signaling. In this study we evaluated whether reintroducing P53 using non-viral gene transfer enhances PTEN-mediated inhibition of PI3K/AKT signaling by cetuximab in PC3 prostate adenocarcinoma cell line bearing p53 and pten mutations. Signaling phosphoproteins expression was analyzed using Bio-Plex phosphoprotein array and western blot. Apoptosis induction was evaluated from BAX expression, caspase-3 activation and DNA fragmentation analyses. The results presented show that p53 and pten gene transfer additionally mediated cell growth inhibition and apoptosis induction by restoral of signaling functionality, which enabled the control of PI3K/AKT and MAPKinase signaling pathways by cetuximab in PC3 cells. These results highlight the interest of the analysis of signaling phosphoproteins expression as molecular predictive markers for response to cetuximab and show that p53 and pten mutations could be key determinants of cell response to cetuximab through the functional impact of these mutations on cell signaling.

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“…The relative contribution of the different inhibitory mechanisms to Akt inactivation may vary among different cell types, as well as between normal and malignant cells. 111 Once again, this brings in the picture of p53 as a master regulator, which pulls simultaneously many strings when apoptosis has to be orchestrated ( Figure 5). …”

Section: P53 Mdm2 and Akt: A Matter Of Balance?mentioning

confidence: 99%

“…The finding that PTEN is a transcriptional target of p53 establishes an additional link in the network: activation of p53 will augment PTEN expression, which will incapacitate Akt and in this manner will further facilitate apoptosis. To make things even more interesting, p53 also represses the expression of the catalytic subunit of PI3 K. 111 Since PI3 K is a critical upstream activator of Akt, this inhibitory effect of p53 will also lead to Akt inactivation, which may cooperate with the induction of PTEN and the degradation of Akt to achieve effective p53-mediated attenuation of Akt function. The relative contribution of the different inhibitory mechanisms to Akt inactivation may vary among different cell types, as well as between normal and malignant cells.…”

Section: P53 Mdm2 and Akt: A Matter Of Balance?mentioning

confidence: 99%

Decision making by p53: life, death and cancer

2003

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The p53 tumor-suppressor plays a critical role in the prevention of human cancer. In the absence of cellular stress, the p53 protein is maintained at low steady-state levels and exerts very little, if any, effect on cell fate. However, in response to various types of stress, p53 becomes activated; this is reflected in elevated protein levels, as well as augmented biochemical capabilities. As a consequence of p53 activation, cells can undergo marked phenotypic changes, ranging from increased DNA repair to senescence and apoptosis. This review deals with the mechanisms that underlie the apoptotic activities of p53, as well as the complex interactions between p53 and central regulatory signaling networks. In p53-mediated apoptosis, the major role is played by the ability of p53 to transactivate specific target genes. The choice of particular subsets of target genes, dictated by covalent p53 modifications and protein-protein interactions, can make the difference between life and apoptotic death of a cell. In addition, transcriptional repression of antiapoptotic genes, as well as transcription-independent activities of p53, can also contribute to the apoptotic effects of p53. Regarding the crosstalk between p53 and signaling networks, this review focuses on the interplay between p53 and two pivotal regulatory proteins: b-catenin and Akt/PKB. Both proteins can regulate p53 as well as be regulated by it. In addition, p53 interacts with the GSK-3b kinase, which serves as a link between Akt and b-catenin. This review discusses how the functional balance between these different interactions might dictate the likelihood of a given cell to become cancerous or be eliminated from the replicative pool, resulting in suppression of cancer.

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p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas

Cited by 191 publications

References 26 publications

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

P53 and PTEN expression contribute to the inhibition of EGFR downstream signaling pathway by cetuximab

Decision making by p53: life, death and cancer

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