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)

v-H-ras transformed C2C12 (C2Ras) myoblasts, overexpressing p21-Ras protein in the Ras-GTP active form, showed a differentiation-defective phenotype when cultured in low serum as compared with C2C12 myoblasts. Accordingly, the purpose of the present study was to delineate the signaling pathways that restore C2Ras myoblasts differentiation. Inhibition of p42/p44-MAPK with the chemical inhibitor PD98059, and activation of AKT/P70S6K and p38-MAPK with insulin, produced growth arrest (precluding the expression of PCNA, cyclin-D1 and retinoblastoma at the hyperphosphorylated state and inducing the expression of the cell cycle inhibitor p21(Cip)) and myogenesis (multinucleated myotubes formation and induction of creatine kinase, caveolin-3 and alpha-actin). Both events were accompanied by down-regulation of AP-1 and up-regulation of NF-kappaB transcriptional activities. Furthermore, inhibition of NF-kappaB transcriptional activity by the use of the proteasome inhibitor MG132 totally precluded differentiation by insulin+PD98059, demonstrating a direct role for NF-kappaB on C2Ras myogenesis. C2Ras myoblasts failed to restore differentiation when rapamycin or PD169316 were added in the presence of insulin+PD98059, indicating that the activation of both P70S6K and p38-MAPK was necessary to reach a fully differentiated phenotype. Finally, transient transfection of a constitutively active Myr-EGFP-AKT-HA construct (in the presence of PD98059) restored C2Ras myogenesis by its ability to activate P70S6K and p38-MAPK. A crosstalk between P70S6K and p38-MAPK was observed under rapamycin treatment in both insulin or active AKT induced myogenesis. Our results are delineating an AKT/P70S6K/p38-MAPK pathway involved in skeletal muscle differentiation.
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PMID:Insulin restores differentiation of Ras-transformed C2C12 myoblasts by inducing NF-kappaB through an AKT/P70S6K/p38-MAPK pathway. 1203 42

Over the past decade, protein kinases have emerged as a group of molecular targets with the potential to be "cancer-specific", allowing the selective targeting of cancer cells versus normal cells. These selective anticancer drugs would eliminate the cytotoxic side effects that are associated with conventional cancer chemotherapy. This article will focus on two emerging and less-explored protein serine/threonine kinase targets: PKB/Akt and checkpoint kinase 1 (Chk1). Protein kinase B/Akts are a group of serine/threonine kinases that are overexpressed in a variety of human tumors. An Akt inhibitor would target the imbalance of pro-versus anti-apoptosis regulation in cancerous as compared to healthy cells. Thus, a greater therapeutic window than conventional cytotoxic chemotherapy is expected. Cell-cycle checkpoints have become attractive targets since some of them, such as the G1/S checkpoint, are defective in most tumor cells. Inhibition of one or more of the remaining checkpoint(s) could make cancerous cells more sensitive than healthy cells toward DNA damaging agents or radiation therapy. Among the checkpoint kinases, Chk1 appears to be an attractive molecular target. Chk1 blocks the activation of the Cdc2-cyclin B kinase complex, and hence entry into mitosis, by disrupting the translocation of the phosphatase Cdc25C from the cyotoplasm to the nucleus. A limited number of small molecule inhibitors in this emerging field and their mode of action will be reviewed.
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PMID:Targeting serine/threonine protein kinase B/Akt and cell-cycle checkpoint kinases for treating cancer. 1217 65

Prostate cancer is one of the most common cancers among men. Recent studies demonstrated that PI3K signaling is an important intracellular mediator which is involved in multiple cellular functions including proliferation, differentiation, anti-apoptosis, tumorigenesis, and angiogenesis. In the present study, we demonstrate that the inhibition of PI3K activity by LY294002, inhibited prostate cancer cell proliferation and induced the G(1) cell cycle arrest. This effect was accompanied by the decreased expression of G(1)-associated proteins including cyclin D1, CDK4, and Rb phosphorylation at Ser780, Ser795, and Ser807/811, whereas expression of CDK6 and beta-actin was not affected by LY294002. The expression of cyclin kinase inhibitor, p21(CIP1/WAF1), was induced by LY294002, while levels of p16(INK4) were decreased in the same experiment. The inhibition of PI3K activity also inhibited the phosphorylation and p70(S6K), but not MAPK. PI3K regulates cell cycle through AKT, mTOR to p70(S6K). The mTOR inhibitor rapamycin has similar inhibitory effects on G(1) cell cycle progression and expression of cyclin D1, CDK4, and Rb phosphorylation. These results suggest that PI3K mediates G(1) cell cycle progression and cyclin expression through the activation of AKT/mTOR/p70(S6K) signaling pathway in the prostate cancer cells.
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PMID:Role of PI3K/AKT/mTOR signaling in the cell cycle progression of human prostate cancer. 1455 32

Ovarian cancer is one of the most common cancers among women. Recent studies demonstrated that the gene encoding the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K) is frequently amplified in ovarian cancer cells. PI3K is involved in multiple cellular functions, including proliferation, differentiation, antiapoptosis, tumorigenesis, and angiogenesis. In this study, we demonstrate that the inhibition of PI3K activity by LY-294002 inhibited ovarian cancer cell proliferation and induced G(1) cell cycle arrest. This effect was accompanied by the decreased expression of G(1)-associated proteins, including cyclin D1, cyclin-dependent kinase (CDK) 4, CDC25A, and retinoblastoma phosphorylation at Ser(780), Ser(795), and Ser(807/811). Expression of CDK6 and beta-actin was not affected by LY-294002. Expression of the cyclin kinase inhibitor p16(INK4a) was induced by the PI3K inhibitor, whereas steady-state levels of p21(CIP1/WAF1) were decreased in the same experiment. The inhibition of PI3K activity also inhibited the phosphorylation of AKT and p70S6K1, but not extracellular regulated kinase 1/2. The G(1) cell cycle arrest induced by LY-294002 was restored by the expression of active forms of AKT and p70S6K1 in the cells. Our study shows that PI3K transmits a mitogenic signal through AKT and mammalian target of rapamycin (mTOR) to p70S6K1. The mTOR inhibitor rapamycin had similar inhibitory effects on G(1) cell cycle progression and on the expression of cyclin D1, CDK4, CDC25A, and retinoblastoma phosphorylation. These results indicate that PI3K mediates G(1) progression and cyclin expression through activation of an AKT/mTOR/p70S6K1 signaling pathway in the ovarian cancer cells.
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PMID:G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells. 1502 55

The genetic mechanisms that control proliferation of childhood musculoskeletal malignancies, notably Ewing's tumor (ET) and rhabdomyosarcoma (RMS), remain largely unknown. Most human cancers appear to overexpress at least one of the G1 cyclins (cyclins D1, D2, D3, E1, and E2) to bypass normal regulation of cell cycle G1 progression. We compared the gene expression profiles of 7 ET and 13 RMS primary tumor samples and found overexpression of cyclin D1 in all 7 ET samples. In contrast, RMS samples expressed higher levels of cyclin D2, cyclin D3, and cyclin E1. This was confirmed by quantitative reverse transcription-polymerase chain reaction and Western blot. The relative roles of RAS-extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3'-kinase (PI3K)-AKT pathways in the regulation of D-type cyclin expression in these tumors were then assessed. Inhibition of either pathway reduced expression of cyclins D1, D2, and D3 in RMS lines, whereas only PI3K inhibitors blocked cyclin D1, D2, and D3 expression in ET lines. Furthermore, PI3K-AKT appeared to regulate D-type cyclin transcription in RMS lines through FKHR and FKHRL1. Finally, the role of the ET-associated EWS-FLI1 fusion gene in regulating D cyclin expression was studied. Inhibition of EWS-FLI1 expression in the TC71 ET line decreased cyclin D1 levels but increased cyclin D3 levels. In contrast, induction of EWS-FLI1 expression in the RD RMS cell line increased cyclin D1 expression but decreased cyclin D3 expression. Our results demonstrate distinct regulation of D-type cyclins in ET and RMS and indicate that EWS-FLI1 can modulate the expression of D-type cyclins independent of cellular backgrounds.
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PMID:Selective usage of D-Type cyclins by Ewing's tumors and rhabdomyosarcomas. 1534 83

The cyclin inhibitory protein p27Kip1 (p27) plays a vital role in regulating cell proliferation in response to the extracellular growth environment. Active proliferation requires the suppression of p27 levels throughout the cell cycle. Late in the cell cycle, p27 degradation requires phosphorylation of Thr 187 by cyclin dependent kinase 2, leading to recognition by the SCF ubiquitin ligase containing the Skp2 F-box protein. Suppression of p27 is also essential for cell proliferation early in the cell cycle, but this occurs independently of Skp2, whose expression is suppressed during G1 phase. In this study, we use a time lapse and quantitative imaging approach to study the connection between proliferative signaling and the degradation of p27 during each cell cycle period in actively cycling cells. Ras activity was required for the suppression of p27 levels throughout the cell cycle, but separate pathways downstream of Ras signaling were required in different cell cycle periods. For example, inhibitors of MEK and phosphatidylinositol-3-kinase induced p27 expression primarily in G1 phase, while inhibitors of AKT activity stimulated these levels primarily in S phase. Skp2 was expressed in a Ras-dependent manner at higher levels late in the cell cycle. Its ablation resulted in higher p27 levels primarily in G2 phase as expected. The fact that separate signaling pathways downstream of Ras function in each cell cycle phase to suppress p27 levels helps explain the vital connection between proliferative signaling, cell cycle control, and p27 expression.
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PMID:P27 expression is regulated by separate signaling pathways, downstream of Ras, in each cell cycle phase. 1547 7

Prostate cancer (PCA) is the most common invasive malignancy and the second leading cause of cancer-related deaths in the US male population. One approach to control this malignancy is its preventive intervention by dietary agents. Inositol hexaphosphate (IP6), a dietary constituent, has shown promising efficacy against various cancers; however, limited studies have been performed with IP6 against PCA. Here, we investigated the growth-inhibitory effect and associated mechanisms of IP6 in androgen-dependent human prostate carcinoma LNCaP cells. IP6 treatment of cells resulted in a strong growth inhibition and an increase in G1 cell population. In mechanistic studies, IP6 resulted in an increase in cyclin-dependent kinase inhibitors (CDKIs) Cip1/p21 and Kip1/p27 levels, together with a decrease in cyclin-dependent kinase (CDK) 4 and cyclin D1 protein levels. An increase in CDKI levels by IP6 also led to a concomitant increase in their interactions with CDK2 and CDK4, together with a strong decrease in the kinase activity of both CDKs. Downstream in CDKI-CDK-cyclin cascade, consistent with its inhibitory effect on CDK kinase activity, IP6 treatment of cells increased hypophosphorylated levels of retinoblastoma (Rb) with a decrease in Rb phosphorylation at serine 780, 807, and 811 sites, and caused a moderate to strong decrease in the levels of transcription factors E2F1, E2F4, and E2F5. In other studies, IP6 caused a dose- and a time-dependent apoptotic death of LNCaP cells, and a decrease in Bcl2 levels, causing a strong increase in Bax versus Bcl2 ratio, as well as an inhibition of constitutively active AKT phosphorylation. Taken together, these molecular alterations provide an insight into IP6-caused growth inhibition, G1 arrest, and apoptotic death of human prostate carcinoma LNCaP cells. Because early clinical PCA growth is an androgen-dependent response, the results of the present study employing androgen-dependent LNCaP cells suggest that IP6 has promise and potential to be effective against PCA.
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PMID:Inositol hexaphosphate inhibits growth and induces G1 arrest and apoptotic death of androgen-dependent human prostate carcinoma LNCaP cells. 1554 74

The RAS-activated RAF-->MEK-->extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3'-kinase (PI3'-kinase)-->PDK1-->AKT signaling pathways are believed to cooperate to promote the proliferation of normal cells and the aberrant proliferation of cancer cells. To explore the mechanisms that underlie such cooperation, we have derived cells harboring conditionally active, steroid hormone-regulated forms of RAF and AKT. These cells permit the assessment of the biological and biochemical effects of activation of these protein kinases either alone or in combination with one another. Under conditions where activation of neither RAF nor AKT alone promoted S-phase progression, coactivation of both kinases elicited a robust proliferative response. Moreover, under conditions where high-level activation of RAF induced G(1) cell cycle arrest, activation of AKT bypassed the arrest and promoted S-phase progression. At the level of the cell cycle machinery, RAF and AKT cooperated to induce cyclin D1 and repress p27(Kip1) expression. Repression of p27(Kip1) was accompanied by a dramatic reduction in KIP1 mRNA and was observed in primary mouse embryo fibroblasts derived from mice either lacking SKP2 or expressing a T187A mutated form of p27(Kip1). Consistent with these observations, pharmacological inhibition of MEK or PI3'-kinase inhibited the effects of activated RAS on the expression of p27(Kip1) in NIH 3T3 fibroblasts and in a panel of bona fide human pancreatic cancer cell lines. Furthermore, we demonstrated that AKT activation led to sustained activation of cyclin/cdk2 complexes that occurred concomitantly with the removal of RAF-induced p21(Cip1) from cyclin E/cdk2 complexes. Cumulatively, these data strongly suggest that the RAF-->MEK-->ERK and PI3'K-->PDK-->AKT signaling pathways can cooperate to promote G(0)-->G(1)-->S-phase cell cycle progression in both normal and cancer cells.
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PMID:Cooperative regulation of the cell division cycle by the protein kinases RAF and AKT. 1557 89

The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) induces growth arrest and apoptosis in various tumor cell lines including non-small cell lung cancer (NSCLC) cells. CD437 binds retinoic acid receptor gamma (RARgamma) selectively, and can enhance receptor-dependent transcriptional activation of various genes. However, some of the effects of this retinoid on cell growth inhibition and apoptosis appear to be receptor-independent. To gain a better understanding of the mechanism by which CD437 exerts its effects, we employed a high throughput western blotting method (PowerBlottrade mark) using 760 monoclonal antibodies to compare the levels of their target cellular signaling proteins in untreated and CD437-treated NSCLC H460 cells. CD437 (1 microM, 24 h) increased the levels of 70 proteins and decreased the levels of 28 proteins. These proteins play a role in fundamental cellular processes including: DNA synthesis and repair, transcription and DNA-binding, cell cycle, apoptosis, cytoskeleton assembly, cell adhesion, endocytosis, growth and signal transduction. Some proteins identified by this approach have been implicated previously in the effect of CD437 (e.g., p53, Bax, cyclin B, CDK2). Additionally we identified proteins that are novel candidates for mediating the cellular responses to CD437 (e.g., FAF1, Bid, caspase 8, cdk1, KAP, NDR, RBBP, 53BP2, Grb2, PLCgamma1, p70s6k, PP2Cdelta, PKBalpha/AKT, PDK1, and several DNA repair enzymes).
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PMID:Identification of protein modulation by the synthetic retinoid CD437 in lung carcinoma cells using high throughput immunoblotting. 1564 34

The abilities of mutated active K-RAS and H-RAS proteins, in an isogenic human carcinoma cell system, to modulate the activity of signaling pathways and cell cycle progression following exposure to ionizing radiation is largely unknown. Loss of K-RAS D13 expression in parental HCT116 colorectal carcinoma cells blunted basal ERK1/2, AKT and JNK1/2 activity by -70%. P38 activity was not detected. Deletion of the allele to express activated K-RAS nearly abolished radiation-induced activation of all signaling pathways. Expression of H-RAS V12 in HCT116 cells lacking an activated RAS molecule (H-RAS V12 cells) restored basal ERK1/2 and AKT activity to that observed in parental cells, but did not restore or alter basal JNK1/2 and p38 activity. In parental cells radiation (1 Gy) caused stronger ERK1/2 pathway activation compared to that of the PI3K/AKT pathway. In H-RAS V12 cells radiation caused stronger PI3K/AKT pathway activation compared to that of the ERK1/2 pathway. Radiation (1 Gy) promoted S phase entry in parental HCT116 cells within 24h, but not in either HCT116 cells lacking K-RAS D13 expression or in H-RAS V12 cells. In parental cells radiation-stimulated S phase entry correlated with ERK1/2-, JNK1/2- and PI3K-dependent increased expression of cyclin D1 and cyclin A, and to a lesser extent cyclin E, 6-24 h after exposure. Cyclin A and cyclin D1 expression were not increased by radiation in cells lacking K-RAS D13 expression or in H-RAS V12 cells. Radiation (1 Gy) modestly enhanced expression of p53, hMDM2 and p21 in parental cells 2-6 h after exposure, which was abolished in cells lacking K-RAS D13 expression. Introduction of H-RAS V12 into cells lacking mutant active RAS partially restored radiation-induced expression of p21 and p53, and enhanced the induction of hMDM2 beyond that observed in parental cells. Collectively, our findings argue that the coordinated activation of multiple signaling pathways, in particular ERK1/2 and JNK1/2, by radiation is required to elevate the expression of G1 and S phase cyclin proteins and to promote S phase entry in human colon carcinoma cells expressing wild type p53. In HCT116 cells H-RAS V12 promotes hMDM2 expression after radiation exposure which correlates with reduced p53 expression and increased cell survival.
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PMID:Radiation-stimulated ERK1/2 and JNK1/2 signaling can promote cell cycle progression in human colon cancer cells. 1565 48


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