Transfection of the E40K into myeloma cells resulted in enhanced tumor cell growth and expression of the PH dominant negative AKT resulted in both inhibition of the IL-6-dependent proliferative response and a decrease in S phase distribution.
While transfection of E40K protected myeloma cells from dexamethasone-induced apoptosis, the dominant negative PH had no effect on the ability of IL-6 to protect these cells from dexamethasone.
Five single-nucleotide polymorphisms, rs3803300, rs1130214, rs3730358, rs2498799 and rs2494732, at the genomic region of AKT1 have been reported to be significantly associated with schizophrenia.
They described a novel point mutation (E17K) in the pleckstrin homology domain (PHD) of the AKT1 gene in human breast, colorectal and ovarian cancers, and demonstrated that it induces leukemia in mice.
They described a novel point mutation (E17K) in the pleckstrin homology domain (PHD) of the AKT1 gene in human breast, colorectal and ovarian cancers, and demonstrated that it induces leukemia in mice.
The same five SNPs used in previous studies of the etiology of schizophrenia (rs2494732, rs2498799, rs3730358, rs1130214, [corrected] and rs3803300) were genotyped in 641 individuals with schizophrenia who had participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project.
They described a novel point mutation (E17K) in the pleckstrin homology domain (PHD) of the AKT1 gene in human breast, colorectal and ovarian cancers, and demonstrated that it induces leukemia in mice.
This was achieved through the retroviral-mediated transduction into normal, primary human esophageal epithelial cells of epidermal growth factor receptor (EGFR), the catalytic subunit of human telomerase (hTERT), and p53(R175H), genes that are frequently altered in human esophageal squamous cell cancer.
This study demonstrated that the AKT1 E17K mutation occurs in breast cancers at a low frequency, and that it is rare in other common cancers, including colorectal, lung, gastric and hepatocellular carcinomas and acute leukaemias.
The activity of the endogenous kinase carrying the E17K mutation immunoprecipitated by tumour tissue was significantly higher compared with the wild-type kinase immunoprecipitated by the adjacent normal tissue as determined both by in vitro kinase assay using a consensus peptide as substrate and by in vivo analysis of the phosphorylation status of AKT1 itself (pT308, pS473) or of known downstream substrates such as GSK3 (pS9/S22) and p27 (T198).
Despite the major role of the AKT/PKB family of proteins in the regulation of many growth and survival mechanisms in the cell, and the increasing evidence suggesting that AKT disruption could play a key role in many human malignancies, no major mutations of AKT genes had been reported, until very recently when Carpten et al reported a novel transforming mutation (E17K) in the pleckstrin homology domain of the AKT1 gene in solid tumours.
Overall, the evidence indicates that the molecular mechanism underlying E17Koncogenesis is a broadened target lipid selectivity that allows high-affinity binding to PI(4,5)P(2).
Our data provide evidence that, although AKT1 mutations are apparently rare in lung cancer (1.9%), the oncogenic properties of E17K-AKT1 may contribute to the development of a fraction of lung carcinoma with squamous histotype (5.5%).
To determine the prevalence of AKT E17K mutations in melanoma, the most aggressive form of skin cancer, we analysed 137 human melanoma specimens and 65 human melanoma cell lines for the previously described activating mutation of AKT1, and for analogous mutations in AKT2 and AKT3.