Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis

Cully, Megan; You, Han; Levine, Arnold J.; Mak, Tak W.

doi:10.1038/nrc1819

Cited by 1,102 publications

(924 citation statements)

References 98 publications

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“…First, it is possible that genes in the PI3K pathway, other than PTEN and PIK3CA, could also be deregulated in CRC. Second, molecular alterations in other signaling pathways (such as MAP kinase) may cross talk and interfere with PI3K signaling (Cully et al, 2006). 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.…”

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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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: 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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“…This initiates a cascade of phosphorylation through Ras/Raf/Mek and ERK (extracellular signal-regulated kinase), which finally translocates to the nucleus and effects transcription. Signaling via phosphatidylinositol 3-kinase (PI3K) of PTEN (phosphatase and tensin homolog on chromosome ten) 215 is shown in blue. PI3K is activated by a multitude of mechanisms, including stimulation by growth factors through receptor tyrosine kinases, such as TrkB.…”

Section: Autism Candidate Genes and Synaptic Functionmentioning

confidence: 99%

“…213 PTEN acts as a phosphatase on phosphatidylinositol triphosphate to antagonize signaling through the PI3K pathway. 215 This pathway (in blue; Figure 1) has an important role in protein synthesis, as well as in the regulation of cell size and proliferation. There are multiple lines of evidence implicating the PI3K pathway in brain development and function.…”

Section: The Conditional Pten-null Mousementioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.

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“…Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a dual protein/lipid phosphatase that can dephosphorylate phosphatidylinositol 3,4,5-triphosphate produced by PI3K, is an important tumor suppressor gene in human cancer (Cully et al, 2006). It is frequently mutated or downregulated in several human cancers and its disruption leads to activation of the Akt pathway (Blanco-Aparicio et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Id-1 activates Akt-mediated Wnt signaling and p27Kip1 phosphorylation through PTEN inhibition

et al. 2008

Oncogene

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Inhibitor of differentiation-1 (Id-1) has been accepted as a putative oncogene to promote oncogenic processes through inactivation of tumor suppressors and activation of growth promoting pathways. Here, we show that Id-1 activates the Akt pathway by inhibition of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) transcription through downregulation of p53. Id-1 negatively regulated both p53 and PTEN at the transcriptional level. In promoter assay with serial deletion and chromatin immunoprecipitation assay, the binding of p53 to the PTEN promoter was reduced by Id-1, suggesting that Id-1 regulates PTEN transcription through its p53 modulation. This led to Akt phosphorylation at Ser473 and the activation of the Akt-mediated canonical Wnt signaling pathway. The glycogen synthase kinase-3b phosphorylation at Ser9, stabilization and nuclear localization of b-catenin, T-cell factor (TCF)/lymphoid enhancer factor transactivation activity and cyclin D1 expression were enhanced by Id-1. On the other hand, Akt-mediated p27 Kip1 phosphorylation at Thr157 and its cytosolic localization were also increased in Id-1 overexpressing MCF7 cells. In conclusion, our results disclose Id-1 as a novel PTEN inhibitor that could activate the Akt pathway and its downstream effectors, the Wnt/TCF pathway and p27 Kip1 phosphorylation and suggest that the oncogenic function of Id-1 may be partly attributed to its PTEN inhibition in human breast carcinogenesis.

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Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis

Cited by 1,102 publications

References 98 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

Advances in behavioral genetics: mouse models of autism

Id-1 activates Akt-mediated Wnt signaling and p27Kip1 phosphorylation through PTEN inhibition

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