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)

The decision between survival and death is an important aspect of cellular regulation during development and malignancy. Central to this regulation is the process of apoptosis, which is conserved in multicellular organisms [1]. A variety of signalling cascades have been implicated in modulation of apoptosis, including the phosphatidylinositol (Pl) 3-kinase pathway. Activation of Pl 3-kinase is protective, and inhibition of this lipid kinase enhances cell death under several conditions including deregulated expression of c-Myc, neurotrophin withdrawal and anoikis [2-7]. Recently, the protective effects of Pl 3-kinase have been linked to its activation of the pleckstrin homology (PH)-domain-containing protein kinase B (PKB or AKT) [8]. PKB/AKT was identified from an oncogene, v-akt, found in a rodent T-cell lymphoma [9]. To initiate a genetic analysis of PKB, we have isolated and characterized a Drosophila PKB/AKT mutant (termed Dakt1) that exhibits ectopic apoptosis during embryogenesis as judged by induction of membrane blebbing, DNA fragmentation and macrophage infiltration. Apoptosis caused by loss of Dakt function is rescued by caspase suppression but is distinct from the previously described reaper/grim/hid functions. These data implicate Dakt1 as a cell survival gene in Drosophila, consistent with cell protection studies in mammals.
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PMID:Genetic analysis of protein kinase B (AKT) in Drosophila. 960 46

The CD53 antigen is a tetraspanin protein of the lymphoid-myeloid lineage, but its implication in biological effects is hardly known. Radioresistant tumor cells express very high levels of this antigen. We have studied the effect of CD53 antigen ligation on the survival response of tumor cells to serum deprivation, a well-known stimulator of cell death that may mimic the tumor environment; for this aim IR938F and Jurkat cells, a B- and T-cell lymphoma, were used. Ligation of CD53 triggers a survival response and reduces the number of cells that enter apoptosis. In CD53- stimulated cells there is a significant reduction in caspase activation, measured by caspase processing of poly ADP-ribose polymerase, as well as a reduction in the fragmentation of DNA. CD53- stimulated cells also have an increase in the level of bcl-X(L) and a reduction of bax protein, two components of the mitochondrial apoptotic pathway, changing their ratio by 24-fold in the direction of survival. This survival signal appears to be mediated by activation of the AKT, as detected by its phosphorylation in Ser473 upon CD53 ligation. The CD53 antigen interactions might contribute to cell survival in poorly vascularized regions of the tumor mass.
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PMID:Apoptosis protection and survival signal by the CD53 tetraspanin antigen. 1260 48

Phosphorylated AKT has been detected in extranodal NK/T-cell lymphoma, nasal type (ENTL). Either interleukin-2 (IL-2) or interleukin-15 (IL-15) could prevent AKT dephosphorylation and apoptosis in the NK-92 cell line model. IL-15, but not IL-2, was preferentially elevated in patients' serum. AKT and IL-15 may be important in ENTL tumor survival.
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PMID:AKT plays a role in the survival of the tumor cells of extranodal NK/T-cell lymphoma, nasal type. 1571 May 91

Multiple copies in T-cell maligancy (MCT-1) is a putative oncogene initially identified in a human T-cell lymphoma. Forced expression of MCT-1 has recently been shown to induce cell transformation and proliferation, as well as to activate survival-related PI-3K/AKT pathways protecting cells from apoptosis. MCT-1 protein is stabilized in response to DNA damage. The impact of MCT-1 overexpression on DNA damage response remains unknown. Here, we show that MCT-1 deregulates cell cycle checkpoints. The phosphorylation of genomic stabilizers H2AX and NBS1 are enhanced in MCT-1-overexpressing cells. Forced expression of MCT-1 significantly increases the number of DNA damage-induced foci involving gamma-H2AX and 53BP1. In MCT-1-overexpressing cells, the proportion of S-phase cell population is preferentially increased after exposure to gamma-irradiation compared to controls. Knockdown of endogenous MCT-1 using an siRNA approach attenuates the H2AX phosphorylation and the G1/S checkpoint defect. Furthermore, MCT-1 is capable of transforming immortalized human mammary epithelial cells and promoting genomic instability. These data shed light on the role of MCT-1 in the cellular response to DNA damage and its involvement in malignant transformation.
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PMID:The MCT-1 oncogene product impairs cell cycle checkpoint control and transforms human mammary epithelial cells. 1589 92

We employed an in vitro hypoxia cell culture model system and gene transfer technology to examine the effect of the decorin gene on cell survival against oxygen and glucose deprivation (OGD). Ectopic expression of decorin in subventricular zone (SVZ) cells from adult male mouse brain and human glioblastoma U-87 cells kept the cells viable against 24 h of OGD. Fewer than 1% of decorin-synthesizing cells were apoptotic after 12 h of OGD. In contrast, 100% of the control cells were apoptotic even after 4 h of OGD. De novo decorin synthesis in SVZ and U-87 cells induced expression of p21, p27 and Ras, AKT (acutely transforming retrovirus AKT8 in rodent T-cell lymphoma), and phosphorylated AKT. Blocking of phosphoinositide 3-kinase (PI-3K), Ras, and the epidermal growth factor receptor with specific inhibitors had no effect on induction of Ras, p21, and p27 at the messenger RNA level in decorin-synthesizing SVZ and U-87 cells. PI-3K inhibitors significantly increased apoptosis in decorin-expressing cells. Our data indicate that induction of p21, p27, Ras, AKT, and phosphorylated AKT by decorin inhibits apoptosis and protects U-87 and SVZ cells against OGD. Therefore, our data suggest that decorin is a potent trophic factor that protects neuronal progenitor cells and glioma cells from OGD.
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PMID:Protection of adult mouse progenitor cells and human glioma cells by de novo decorin expression in an oxygen- and glucose-deprived cell culture model system. 1646 81

Among the many oncogenic variants of the anaplastic lymphoma kinase (ALK), nucleophosmin 1 (NPM)/ALK fusion protein expressed in the subset of T-cell lymphoma (ALK(+)TCL) is currently the best characterized. NPM/ALK activates several signal transduction pathways, including PI3K/AKT, MEK/ERK, mTORC1, STAT3, and STAT5b. In turn, the pathways modulate expression and function of many genes and proteins involved in the key cellular functions such as proliferation, growth, survival, metabolism, and angiogenesis. Recent data indicate that NPM/ALK also promotes immune evasion of the ALK(+)TCL by inducing through STAT3 activation the expression of immunosuppressive cytokines interleukin-10 (IL-10) and transforming growth factor-beta (TGFss) and cell surface protein CD274 (PD-L1, B7-H1). In addition, NPM/ALK protects its own expression by mediating via STAT3 and at least one member of the DNA methyltransferase family DNMT1 epigenetic silencing of the SHP-1 and STAT5a genes. In ALK+TCL cells, SHP-1 and STAT5a proteins act as potent tumor suppressors by promoting degradation of the NPM/ALK protein and inhibiting expression of the NPM/ALK gene, respectively. These findings provide further rationale to therapeutically target ALK and its effector proteins, foremost STAT3. They also suggest that immunotherapeutic approaches to ALK(+)TCL and, possibly, other ALK-driven malignancies may require inhibition of ALK and STAT3 to achieve the optimal clinical efficacy.
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PMID:Anaplastic lymphoma kinase (ALK)-induced malignancies: novel mechanisms of cell transformation and potential therapeutic approaches. 1939 33

Biopsies and cell lines of natural killer/T-cell lymphoma, nasal type (NKTCL) were subject to combined gene expression profiling and array-based comparative genomic hybridization analyses. Compared with peripheral T-cell lymphoma, not otherwise specified, NKTCL had greater transcript levels for NK-cell and cytotoxic molecules, especially granzyme H. Compared with normal NKcells, tumors were closer to activated than resting cells and overexpressed several genes related to vascular biology, Epstein-Barr Virus-induced genes, and PDGFRA. Notably, platelet-derived growth factor receptor alpha and its phosphorylated form were confirmed at the protein level, and in vitro the MEC04 NKTCL cell line was sensitive to imatinib. Deregulation of the AKT, Janus kinase-signal transducers and activators of transcription, and nuclear factor-kappaB pathways was corroborated by nuclear expression of phosphorylated AKT, signal transducers and activators of transcription 3, and RelA in NKTCL, and several deregulated genes in these pathways mapped to regions of recurrent copy number aberrations (AKT3 [1q44], IL6R [1q21.3], CCL2 [17q12], TNFRSF21 [6p12.3]). Several features of NKTCL uncovered by this analysis suggest perturbation of angiogenic pathways. Integrative analysis also evidenced deregulation of the tumor suppressor HACE1 in the frequently deleted 6q21 region. This study highlights emerging oncogenic pathways in NKTCL and identifies novel diagnostic and therapeutic targets.
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PMID:Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type. 1996 20

Human cancers, including acute myeloid leukemia (AML), commonly display constitutive phosphoinositide 3-kinase (PI3K) AKT signaling. However, the exact role of AKT activation in leukemia and its effects on hematopoietic stem cells (HSCs) are poorly understood. Several members of the PI3K pathway, phosphatase and tensin homolog (Pten), the forkhead box, subgroup O (FOXO) transcription factors, and TSC1, have demonstrated functions in normal and leukemic stem cells but are rarely mutated in leukemia. We developed an activated allele of AKT1 that models increased signaling in normal and leukemic stem cells. In our murine bone marrow transplantation model using a myristoylated AKT1 (myr-AKT), recipients develop myeloproliferative disease, T-cell lymphoma, or AML. Analysis of the HSCs in myr-AKT mice reveals transient expansion and increased cycling, associated with impaired engraftment. myr-AKT-expressing bone marrow cells are unable to form cobblestones in long-term cocultures. Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) rescues cobblestone formation in myr-AKT-expressing bone marrow cells and increases the survival of myr-AKT mice. This study demonstrates that enhanced AKT activation is an important mechanism of transformation in AML and that HSCs are highly sensitive to excess AKT/mTOR signaling.
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PMID:Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. 2000 87

Growth factors and many oncogenes activate the lipid kinase phosphoinositide 3-kinase (PI3K), initiating a signaling cascade that includes the protein kinases AKT and target of rapamycin (TOR). The PI3K/AKT/TOR signaling pathway is a significant contributor to disease in various human cancers, including hematologic malignancies. Here we discuss different strategies to inhibit TOR for the treatment of leukemia, lymphoma, and myeloma. The TOR enzyme exists in two complexes in cells, TORC1 and TORC2. The majority of preclinical and clinical efforts to target TOR have involved using rapamycin and its analogs (rapalogs), which suppress TORC1 only partially and do not acutely inhibit TORC2. A new class of small molecules targeting the ATP-binding site of the TOR kinase, termed active-site TOR inhibitors (asTORi), achieves greater inhibition of both TOR complexes, resulting in broader suppression of the PI3K/AKT/TOR signaling network. Preclinical evidence suggests that asTORi have greater efficacy than rapalogs in Philadelphia chromosome-positive acute lymphoblastic leukemia and in T-cell lymphoma. These agents also show greater tolerability in animal models relative to rapalogs or inhibitors of PI3K. These findings encourage broader evaluation of asTORi efficacy in acute myeloid leukemia, B-cell lymphoma, myeloma, and other blood cancers.
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PMID:Target of rapamycin signaling in leukemia and lymphoma. 2082 59

The distal-less homeobox gene (dlx) 5 encodes a transcription factor that controls jaw formation and appendage differentiation during embryonic development. We had previously found that Dlx5 is overexpressed in an Akt2 transgenic model of T-cell lymphoma. To investigate if DLX5 is involved in human cancer, we screened its expression in the NCI 60 cancer cell line panel. DLX5 was frequently upregulated in cell lines derived from several tumor types, including ovarian cancer. We next validated its upregulation in primary ovarian cancer specimens. Stable knockdown of DLX5 by lentivirus-mediated transduction of short hairpin RNA (shRNA) resulted in reduced proliferation of ovarian cancer cells due to inhibition of cell cycle progression in connection with the downregulation of cyclins A, B1, D1, D2, and E, and decreased phosphorylation of AKT. Cell proliferation resumed following introduction of a DLX5 cDNA harboring wobbled mutations at the shRNA-targeting sites. Cell proliferation was also rescued by transduction of a constitutively active form of AKT. Intriguingly, downregulation of IRS-2 and MET contributed to the suppression of AKT signaling. Moreover, DLX5 was found to directly bind to the IRS-2 promoter and augmented its transcription. Knockdown of DLX5 in xenografts of human ovarian cancer cells resulted in markedly diminished tumor size. In addition, DLX5 was found to cooperate with HRAS in the transformation of human ovarian surface epithelial cells. Together, these data suggest that DLX5 plays a significant role in the pathogenesis of some ovarian cancers.
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PMID:Upregulation of DLX5 promotes ovarian cancer cell proliferation by enhancing IRS-2-AKT signaling. 2104 56


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