Adam Naguib

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States

Are you Adam Naguib?

Claim your profile

Publications (8)62.48 Total impact

  • Adam Naguib, Lloyd C Trotman
    [Show abstract] [Hide abstract]
    ABSTRACT: PTEN loss drives many cancers and recent genetic studies reveal that often PTEN is antagonised at the protein level without alteration of DNA or RNA expression. This scenario can already cause malignancy, because PTEN is haploinsufficient. We here review normally occurring mechanisms of PTEN protein regulation and discuss three processes where PTEN plasticity is needed: ischaemia, development, and wound healing. These situations demand transient PTEN suppression, whereas cancer exploits them for continuous proliferation and survival advantages. Therefore, increased understanding of PTEN plasticity may help us better interpret tumour development and ultimately lead to drug targets for PTEN supporting cancer therapy.
    Trends in cell biology 04/2013; · 12.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The tumour suppressor APC is the most commonly altered gene in colorectal cancer (CRC). Genetic and epigenetic alterations of APC may therefore be associated with dietary and lifestyle risk factors for CRC. Analysis of APC mutations in the extended mutation cluster region (codons 1276-1556) and APC promoter 1A methylation was performed on 185 archival CRC samples collected from participants of the European Prospective Investigation into Cancer (EPIC)-Norfolk study, with the aim of relating these to high-quality seven-day dietary and lifestyle data collected prospectively. Truncating APC mutations (APC(+) ) and promoter 1A methylation (PM(+) ) were identified in 43% and 23% of CRCs analysed, respectively. Distal CRCs were more likely than proximal CRCs to be APC(+) or PM(+) (p = 0.04). APC(+) CRCs were more likely to be moderately/well differentiated and microsatellite stable than APC(-) CRCs (p = 0.05 and 0.03). APC(+) CRC cases consumed more alcohol than their counterparts (p = 0.01) and PM(+) CRC cases consumed lower levels of folate and fibre (p = 0.01 and 0.004). APC(+) or PM(+) CRC cases consumed higher levels of processed meat and iron from red meat and red meat products (p = 0.007 and 0.006). Specifically, CRC cases harbouring GC-to-AT transition mutations consumed higher levels of processed meat (35 versus 24 g/day, p = 0.04) and iron from red meat and red meat products (0.8 versus 0.6 mg/day, p = 0.05). In a logistic regression model adjusted for age, sex and cigarette-smoking status, each 19 g/day (1SD) increment increase in processed meat consumption was associated with cases with GC-to-AT mutations (OR 1.68, 95% CI 1.03-2.75). In conclusion, APC(+) and PM(+) CRCs may be influenced by diet and GC-to-AT mutations in APC are associated with processed meat consumption, suggesting a mechanistic link with dietary alkylating agents, such as N-nitroso compounds. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    The Journal of Pathology 08/2012; 228(3):405-15. · 7.59 Impact Factor
  • Source
    02/2012; , ISBN: 978-953-51-0028-7
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: PTEN (phosphatase and tensin homologue deleted on chromosome TEN) is the major negative regulator of phosphatidylinositol 3-kinase signaling and has cell-specific functions including tumor suppression. Nuclear localization of PTEN is vital for tumor suppression; however, outside of cancer, the molecular and physiological events driving PTEN nuclear entry are unknown. In this paper, we demonstrate that cytoplasmic Pten was translocated into the nuclei of neurons after cerebral ischemia in mice. Critically, this transport event was dependent on a surge in the Nedd4 family-interacting protein 1 (Ndfip1), as neurons in Ndfip1-deficient mice failed to import Pten. Ndfip1 binds to Pten, resulting in enhanced ubiquitination by Nedd4 E3 ubiquitin ligases. In vitro, Ndfip1 overexpression increased the rate of Pten nuclear import detected by photobleaching experiments, whereas Ndfip1(-/-) fibroblasts showed negligible transport rates. In vivo, Ndfip1 mutant mice suffered larger infarct sizes associated with suppressed phosphorylated Akt activation. Our findings provide the first physiological example of when and why transient shuttling of nuclear Pten occurs and how this process is critical for neuron survival.
    The Journal of Cell Biology 01/2012; 196(1):29-36. · 10.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hyperactivation of the PI 3-kinase/AKT pathway is a driving force of many cancers. Here we identify the AKT-inactivating phosphatase PHLPP1 as a prostate tumor suppressor. We show that Phlpp1-loss causes neoplasia and, on partial Pten-loss, carcinoma in mouse prostate. This genetic setting initially triggers a growth suppressive response via p53 and the Phlpp2 ortholog, and reveals spontaneous Trp53 inactivation as a condition for full-blown disease. Surprisingly, the codeletion of PTEN and PHLPP1 in patient samples is highly restricted to metastatic disease and tightly correlated to deletion of TP53 and PHLPP2. These data establish a conceptual framework for progression of PTEN mutant prostate cancer to life-threatening disease.
    Cancer cell 08/2011; 20(2):173-86. · 25.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The K-RAS oncogene is widely mutated in human cancers. Activating mutations in K-RAS give rise to constitutive signalling through the MAPK/ERK and PI3K/AKT pathways promoting increased cell division, reduced apoptosis and transformation. The majority of activating mutations in K-RAS are located in codons 12 and 13. In a human colorectal cancer we identified a novel K-RAS co-mutation that altered codons 19 and 20 resulting in transitions at both codons (L19F/T20A) in the same allele. Using focus forming transformation assays in vitro , we showed that co-mutation of L19F/T20A in K-RAS demonstrated intermediate transforming ability that was greater than that of individual L19F and T20A mutants, but less than that of G12D and G12V K-RAS mutants. This demonstrated the synergistic effects of co-mutation of codons 19 and 20 and illustrated that co-mutation of these codons is functionally significant.
    Journal of Molecular Signaling 03/2011; 6:2.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The PTEN tumour suppressor gene and PIK3CA proto-oncogene encode proteins which contribute to regulation and propagation of signal transduction through the PI3K/AKT signalling pathway. This study investigates the prevalence of loss of PTEN expression and mutations in both PTEN and PIK3CA in colorectal cancers (CRC) and their associations with tumour clinicopathological features, lifestyle factors and dietary consumptions. 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for PTEN and PIK3CA mutations by DNA sequencing and PTEN expression changes by immunohistochemistry. Dietary and lifestyle data were collected prospectively using seven day food diaries and lifestyle questionnaires. Mutations in exons 7 and 8 of PTEN were observed in 2.2% of CRC and PTEN loss of expression was identified in 34.9% CRC. Negative PTEN expression was associated with lower blood low-density lipoprotein concentrations (p = 0.05). PIK3CA mutations were observed in 7% of cancers and were more frequent in CRCs in females (p = 0.04). Analysis of dietary intakes demonstrated no link between PTEN expression status and any specific dietary factor. PTEN expression negative, proximal CRC were of more advanced Dukes' stage (p = 0.02) and poor differentiation (p < 0.01). Testing of the prevalence of PIK3CA mutations and loss of PTEN expression demonstrated that these two events were independent (p = 0.55). These data demonstrated the frequent occurrence (34.9%) of PTEN loss of expression in colorectal cancers, for which gene mutations do not appear to be the main cause. Furthermore, dietary factors are not associated with loss of PTEN expression. PTEN expression negative CRC were not homogenous, as proximal cancers were associated with a more advanced Dukes' stage and poor differentiation, whereas distal cancers were associated with earlier Dukes' stage.
    BMC Cancer 01/2011; 11:123. · 3.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BRAF and K-ras proto-oncogenes encode components of the ERK signalling pathway and are frequently mutated in colorectal cancer. This study investigates the associations between BRAF and K-ras mutations and clinicopathological, lifestyle and dietary factors in colorectal cancers. 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for BRAF and K-ras mutations. Diet and lifestyle data were collected prospectively using seven day food diaries. BRAF V600E mutation was found in 15.6% of colorectal cancers but at higher frequencies in cancers with proximal location, poor differentiation and microsatellite instability (MSI) (all p < 0.001). K-ras mutation (mostly in codons 12 and 13) was found in 22.0% of colorectal cancers but at higher frequencies in cancers of more advanced Dukes' stage (p = 0.001), microsatellite stable (MSS) status (p = 0.002) and in individuals with lower blood high-density lipoprotein concentrations (p = 0.04). Analysis of dietary factors demonstrated no link between BRAF mutation and any specific dietary constituent, however, K-ras mutation was found at higher frequencies in individuals with higher white meat consumption (p < 0.001). Further analysis of specific mutation type demonstrated that G to A transitions in K-ras were observed at higher frequencies in individuals consuming lower amounts of fruit (p = 0.02). These data support the model of BRAF and K-ras mutations arising in distinct colorectal cancer subsets associated with different clinicopathological and dietary factors, acting as mutually exclusive mechanisms of activation of the same signalling pathway.
    BMC Cancer 03/2010; 10:99. · 3.33 Impact Factor

Publication Stats

101 Citations
62.48 Total Impact Points


  • 2013
    • Cold Spring Harbor Laboratory
      Cold Spring Harbor, New York, United States
  • 2012
    • Medical Research Council (UK)
      Londinium, England, United Kingdom
  • 2010–2011
    • University of Cambridge
      • Department of Pathology
      Cambridge, ENG, United Kingdom