Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

About 30% of patients with acute myeloid leukemia (AML) harbour mutations of the receptor tyrosine kinase FLT3, mostly internal tandem duplications (ITD) and point mutations of the second tyrosine kinase domain (TKD). It was the aim of this study to comprehensively analyze clinical and functional properties of various FLT3 mutants. In 672 normal karyotype AML patients FLT3-ITD, but not FLT3-TKD mutations were associated with a worse relapse free and overall survival in multivariate analysis. In paired diagnosis-relapse samples FLT3-ITD showed higher stability (70%) compared to FLT3-TKD (30%). In vitro, FLT3-ITD induced a strong activating phenotype in Ba/F3 cells. In contrast, FLT3-TKD mutations and other point mutations--including two novel mutations--showed a weaker but clear gain-of-function phenotype with gradual increase in proliferation and protection from apoptosis. The pro-proliferative capacity of the investigated FLT3 mutants was associated with cell surface expression and tyrosine 591 phosphorylation of the FLT3 receptor. Western blot experiments revealed STAT5 activation only in FLT3-ITD positive cell lines, in contrast to FLT3-non-ITD mutants, which displayed an enhanced signal of AKT and MAPK activation. Gene expression analysis revealed distinct difference between FLT3-ITD and FLT3-TKD for STAT5 target gene expression as well as deregulation of SOCS2, ENPP2, PRUNE2 and ART3. FLT3-ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. Although poor prognosis in AML is only associated with FLT3-ITD, all activating FLT3 mutations can contribute to leukemogenesis and are thus potential targets for therapeutic interventions.
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PMID:Activating FLT3 mutants show distinct gain-of-function phenotypes in vitro and a characteristic signaling pathway profile associated with prognosis in acute myeloid leukemia. 2460 88

BCH motif-containing molecule at the carboxyl terminal region 1 (BMCC1)/PRUNE2 is highly expressed in patients with favorable neuroblastoma (NB), encoding a multifunctional scaffold protein that modulates several signaling networks including RhoA and AKT pathways. Accumulating evidence suggests that BMCC1 acts as a tumor-suppressor. In this study, we addressed molecular mechanism underlying transcriptional regulation of BMCC1 in NBs. We found that transcription factor E2F1 was recruited to E2F-binding site in the promoter region of BMCC1 gene. Indeed, overexpression of E2F1 resulted in an increase in the expression level of BMCC1 in NB cell lines. On the other hand, knockdown of E2F1 in NB cells yielded down-regulation of BMCC1. Also, we showed that BMCC1 and E2F1 were simultaneously induced at G1 to S phase transition. Therefore, we conclude that E2F1 directly facilitated BMCC1 transcription. Taking together, these results suggest that BMCC1 induced by E2F1 acts as a tumor suppressor through its pro-apoptotic function, resulted in favorable prognosis of NB.
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PMID:Transcriptional regulation of BMCC1 mediated by E2F1 in neuroblastoma cells. 2745 42

Parathyroid carcinoma (PC) is a rare neoplasia difficult to diagnose preoperatively. It mainly occurs as a sporadic disease but also as part of familial PHPT. At variance with patients with the benign counterpart, the phenotype of these patients is characterized by a severe primary hyperparathyroidism (PHPT). The clinical features are mostly due to the effects of the excessive secretion of PTH by the functioning tumor and hypercalcemia rather than to the tumor burden. The prognosis is poor and unmanageable hypercalcemia accounts for death in the majority of cases. The best chance of cure is surgery, although persistent or recurrent disease occurs in about 50% of patients. Somatic loss-of-function mutations of CDC73 gene, encoding parafibromin, are the most frequent genetic alterations occurring in PCs. Mutations of the PRUNE2 gene, alterations of the PI3K/AKT/mTOR pathway and amplification of the CCND1 gene have been recently detected in PCs. Alteration of microRNA profile and methylation pattern have been identified in PCs. The recent studies have better defined the genomic landscape of PCs and represent major progress toward a full molecular characterization of this neoplasia and development of novel therapeutic options.
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PMID:Parathyroid carcinoma: a clinical and genetic perspective. 2894 21