Mutations in a signalling pathway

Parsons, D. Williams; Wang, Tian Li; Samuels, Yardena; Bardelli, Alberto; Cummins, Jordan M.; DeLong, Laura J.; Silliman, Natalie; Ptak, Janine; Szabo, Steve; Willson, James K.V.; Markowitz, Sanford D.; Kinzler, Kenneth W.; Vogelstein, Bert; Lengauer, Christoph; Velculescu, Victor E.

doi:10.1038/436792a

Cited by 527 publications

(407 citation statements)

References 9 publications

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“…This gene is mutated in 15-30% of colorectal cancers, with hotspots identified in exons 1, 2, 9 and 20, and mutated p110a proteins have shown in vitro a gain of enzymatic function by activating the AKT signalling in the absence of growth factors and are thus oncogenic in cell culture and animal models (Samuels et al, 2004;Ikenoue et al, 2005;Kang et al, 2005). In colorectal cancer, PIK3CA mutations occur more frequently in women, and in the proximal part of the colon (Benvenuti et al, 2008;Barault et al, 2008b), a double mutation of the gene is observed in 6-9% of the mutated cases (Samuels et al, 2004;Barault et al, 2008b) and there is a significant concomitant occurrence of KRAS and PIK3CA mutations (Parsons et al, 2005;Velho et al, 2005;Barault et al, 2008b).…”

Section: Mapk Pathway Mutationsmentioning

confidence: 99%

Oncogenic mutations as predictive factors in colorectal cancer

2010

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Section: Mapk Pathway Mutationsmentioning

confidence: 99%

Oncogenic mutations as predictive factors in colorectal cancer

2010

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“…However, the AKT2 gene is amplified in about PTEN/PI3K signaling perturbations in cancer M Keniry and R Parsons 10% of ovarian cancers and 3% of breast cancers (Bellacosa et al, 1995;Parsons et al, 2005). A recent study has also reported that AKT1 is mutated within the Pleckstrin Homology Domain (E17K) in 8% of breast, 6% of colorectal and 2% of ovarian cancers that were examined (Carpten et al, 2007).…”

Section: Perturbations Of Pten Signaling In Cancermentioning

confidence: 99%

The role of PTEN signaling perturbations in cancer and in targeted therapy

2008

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The PTEN tumor suppressor was discovered by its homozygous deletion and other mutations in cancer. Since then, PTEN has been shown to be a non-redundant, evolutionarily conserved phosphatase whose function affects diverse cellular progresses such as cell cycle progression, cell proliferation, chemotaxis, apoptosis, aging, muscle contractility, DNA damage response, angiogenesis and cell polarity. In accordance with its ability to influence multiple crucial cellular processes, PTEN has a major role in the pathogenesis of numerous diseases such as diabetes, autism and almost every cancer examined. This review will discuss the diverse ways in which PTEN signaling is modified in cancer, and how these changes correlate with and might possibly affect the action of targeted chemotherapy.

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“…Different results indicate isoform-specific functions in tumor cells. For instance, mutations and amplifications in epithelial tumors have been detected mainly in Akt2 and very rarely in Akt1 (Bellacosa et al, 2004;Parsons et al, 2005). Overexpression of Akt2, but not Akt1, increased the invasiveness of a tumor breast cell line in vitro and in animal models (Arboleda et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Akt2 interacts with Snail1 in the E-cadherin promoter

et al. 2011

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Snail1 is a transcriptional factor essential for triggering epithelial-to-mesenchymal transition. Moreover, Snail1 promotes resistance to apoptosis, an effect associated to PTEN gene repression and Akt stimulation. In this article we demonstrate that Snail1 activates Akt at an additional level, as it directly binds to and activates this protein kinase. The interaction is observed in the nucleus and increases the intrinsic Akt activity. We determined that Akt2 is the isoform interacting with Snail1, an association that requires the pleckstrin homology domain in Akt2 and the C-terminal half in Snail1. Snail1 enhances the binding of Akt2 to the E-cadherin (CDH1) promoter and Akt2 interference prevents Snail1 repression of CDH1 gene. We also show that Snail1 binding increases Akt2 intrinsic activity on histone H3 and have identified Thr45 as a residue modified on this protein. Phosphorylation of Thr45 in histone H3 is sensitive to Snail1 and Akt2 cellular levels; moreover, Snail1 upregulates the binding of phosphoThr45 histone H3 to the CDH1 promoter. These results uncover an unexpected role of Akt2 in transcriptional control and point out to phosphorylation of Thr45 in histone H3 as a new epigenetic mark related to Snail1 and Akt2 action.

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Mutations in a signalling pathway

Cited by 527 publications

References 9 publications

Oncogenic mutations as predictive factors in colorectal cancer

Oncogenic mutations as predictive factors in colorectal cancer

The role of PTEN signaling perturbations in cancer and in targeted therapy

Akt2 interacts with Snail1 in the E-cadherin promoter

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