Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stem cell factor (SCF)/c-kit plays an important role in the regulation of hematopoiesis, melanogenesis, and spermatogenesis. In the testis, the SCF/c-kit system is believed to regulate germ cell proliferation, meiosis, and apoptosis. Studies with type A spermatogonia in vivo and in vitro have indicated that SCF induces DNA synthesis and proliferation. However, the signaling pathway for this function of SCF/c-kit has not been elucidated. We now demonstrate that SCF activates phosphoinositide 3-kinase (PI3-K) and p70 S6 kinase (p70S6K) and that rapamycin, a FRAP/mammalian target of rapamycin-dependent inhibitor of p70S6K, completely inhibited bromodeoxyuridine incorporation induced by SCF in primary cultures of spermatogonia. SCF induced cyclin D3 expression and phosphorylation of the retinoblastoma protein through a pathway that is sensitive to both wortmannin and rapamycin. Furthermore, AKT, but not protein kinase C-zeta, is used by SCF/c-kit/PI3-K to activate p70S6K. Dominant negative AKT-K179M completely abolished p70S6K phosphorylation induced by the constitutively active PI3-K catalytic subunit p110. Constitutively active v-AKT highly phosphorylated p70S6K, which was totally inhibited by rapamycin. Thus, SCF/c-kit uses a rapamycin-sensitive PI3-K/AKT/p70S6K/cyclin D3 pathway to promote spermatogonial cell proliferation.
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PMID:Stem cell factor/c-kit up-regulates cyclin D3 and promotes cell cycle progression via the phosphoinositide 3-kinase/p70 S6 kinase pathway in spermatogonia. 1084 22

In the early phase of adipocyte differentiation, transient increase of DNA synthesis, called clonal expansion, and transient hyperphosphorylation of retinoblastoma protein (Rb) are observed. We investigated the role of these phenomena in insulin-induced adipocyte differentiation of 3T3-L1 cells. Insulin-induced clonal expansion, Rb phosphorylation and adipocyte differentiation were all inhibited by the PI 3-kinase inhibitors and rapamycin, but not the MEK inhibitor, whereas the MEK inhibitor, but not PI 3-kinase inhibitors or rapamycin, decreased c-fos induction. We conclude that insulin induces hyperphosphorylation of Rb via PI 3-kinase and mTOR dependent pathway, which promotes clonal expansion and adipocyte differentiation of 3T3-L1 cells.
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PMID:Retinoblastoma protein phosphorylation via PI 3-kinase and mTOR pathway regulates adipocyte differentiation. 1094 51

The high frequency of mutations in cancer cells which result in altered cell cycle regulation and growth signal transduction, conferring a proliferative advantage, indicates that many of these aberrant mechanisms may be strategic targets for cancer therapy. The macrolide fungicide rapamycin, a natural product with potent antimicrobial, immunosuppressant, and anti-tumor properties, inhibits the translation of key mRNAs of proteins required for cell cycle progression from G1 to S phase. Rapamycin binds intracellularly to the immunophilin FK506 binding protein 12 (FKBP12), and the resultant complex inhibits the protein kinase activity of a protein kinase termed mammalian target of rapamycin (mTOR). The inhibition of mTOR, in turn, blocks signals to two separate downstream pathways which control the translation of specific mRNAs required for cell cycle traverse from G1 to S phase. Blocking mTOR affects the activity of the 40S ribosomal protein S6 kinase (p70s6k) and the function of the eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), leading to growth arrest in the the G1 phase of the cell cycle. In addition to its actions on p70s6k and 4E-BP1, rapamycin prevents cyclin-dependent kinase activation, inhibits retinoblastoma protein (pRb) phosphorylation, and accelerates the turnover of cyclin D1 that leads to a deficiency of active cdk4/cyclin D1 complexes, all of which can inhibit cell cycle traverse at the G1/S phase transition. Both rapamycin and CCI-779, an ester analog of rapamycin with improved pharmaceutical properties and aqueous solubility, have demonstrated impressive activity against a broad range of human cancers growing in tissue culture and in human tumor xenograft models, which has supported the development of compounds targeting rapamycin-sensitive signal-transduction pathways. CCI-779 has completed several phase I clinical evaluations and is currently undergoing broad disease-directed efficacy studies. The agent appears to be well tolerated at doses that have resulted in impressive anti-tumor activity in several types of refractory neoplasms. Important challenges during clinical development include the definition of a recommended dose range associated with optimal biological activity and maximal therapeutic indices, as well as the ability to predict which tumors will be sensitive or resistant to CCI-779.
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PMID:The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. 1142 55

We have previously demonstrated that N-acetylleucine amide, a derivative of L-leucine, inhibits leucine-induced p70(S6k) activation in a rat hepatoma cell line. In the present study, we investigated whether N-acetylleucine amide is capable of inhibiting amino acid-mTOR signaling. N-Acetylleucine amide caused cell cycle arrest at G1 stage in Jurkat cells, a human leukemia T cell line, concomitant with the inhibition of serum-induced p70(S6k) activation and p27 degradation. Treatment of Jurkat cells with this compound also exhibited dephosphorylation of retinoblastoma protein. These effects are similar to the inhibitory effects of rapamycin on amino acid-mTOR signaling pathway and suggest that N-acetylleucine amide acts as a rapamycin-like reagent to inhibit cell cycle progression in Jurkat cells.
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PMID:Inhibition of amino acid-mTOR signaling by a leucine derivative induces G1 arrest in Jurkat cells. 1256 77

Unlike a large number of cell types that undergo terminal differentiation associated with permanent withdrawal from the cell cycle, mature quiescent hepatocytes retain high proliferative potential. We report here a specific behavior of members of the Cip/Kip family of cyclin-dependent kinase (Cdk) inhibitors during development of the rat liver and proliferation of normal hepatocytes. Expression of p21, p27, and p57 transcripts and proteins was downregulated during the differentiation process to low or undetectable levels in adult liver. In contrast to p27, p21 protein increased in a mitogen-dependent manner in isolated hepatocytes and its expression pattern correlated with that of cyclin D1. In proliferating hepatocytes, p21 was predominantly associated with cyclin D1, these proteins were colocalized in the nucleus and p21-associated retinoblastoma protein (pRb) kinase activity increased in parallel with that of cyclin D1. Overexpression of p21 in mitogen-stimulated hepatocytes reduced DNA synthesis. In contrast, inhibition of p21 expression by antisense or small interfering RNAs oligonucleotides accelerated S phase entry. Finally, expression of p21 and cyclin D1, but not p27 proteins was regulated by MAPK kinase/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase-ferric-reducing ability power/mammalian target of rapamycin signal transduction pathways. In conclusion, these results demonstrate a specific and differential regulation of p21 and p27 during hepatocyte differentiation and proliferation that may contribute to the control of quiescent differentiated hepatic cell proliferating activity.
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PMID:Regulation and role of p21 and p27 cyclin-dependent kinase inhibitors during hepatocyte differentiation and growth. 1264 20

The mammalian target of rapamycin (mTOR), a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway that mediates cell survival and proliferation, is a prime strategic target for anticancer therapeutic development. By targeting mTOR, the immunosuppressant and antiproliferative agent rapamycin inhibits signals required for cell cycle progression, cell growth, and proliferation. Both rapamycin and novel rapamycin analogues with more favorable pharmaceutical properties, such as CCI-779, RAD 001, and AP23573, are highly specific inhibitors of mTOR. In essence, these agents gain function by binding to the immunophilin FK506 binding protein 12 and the resultant complex inhibits the activity of mTOR. Because mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1, rapamycin-like compounds block the actions of these downstream signaling elements, which results in cell cycle arrest in the G1 phase. Rapamycin and its analogues also prevent cyclin-dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which potentially contribute to the prominent inhibitory effects of rapamycin at the G1/S boundary of the cell cycle. Rapamycin and rapamycin analogues have demonstrated impressive growth-inhibitory effects against a broad range of human cancers, including breast cancer, in preclinical and early clinical evaluations. In breast cancer cells, PI3K/Akt and mTOR pathways seem to be critical for the proliferative responses mediated by the epidermal growth factor receptor, the insulin growth factor receptor, and the estrogen receptor. Furthermore, these pathways may be constitutively activated in cancers with many types of aberrations, including those with loss of PTEN suppressor gene function. Therefore, the development of inhibitors of mTOR and related pathways is a rational therapeutic strategy for breast and other malignancies that possess a wide range of aberrant molecular constituents. This review will summarize the principal mechanisms of action of rapamycin and rapamycin derivatives, as well as the potential utility of these agents as anticancer therapeutic agents with an emphasis on breast cancer. The preliminary results of early clinical evaluations with rapamycin analogues and the unique developmental challenges that lie ahead will also be discussed.
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PMID:Mammalian target of rapamycin: a new molecular target for breast cancer. 1286 41

The mammalian target of rapamycin (mTOR) is a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway, which mediates cell survival and proliferation. mTOR regulates essential signal-transduction pathways, is involved in the coupling of growth stimuli with cell cycle progression, and initiates mRNA translation in response to favorable nutrient environments. mTOR is involved in regulating many aspects of cell growth, including membrane traffic, protein degradation, protein kinase C signaling, ribosome biogenesis, and transcription. Because mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein 1, its inhibitors cause G1-phase cell cycle arrest. Inhibitors of mTOR also prevent cyclin dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause G1-phase arrest. It is known that the phosphatase and tensin homologue tumor suppressor gene (PTEN) plays a major role in embryonic development, cell migration, and apoptosis. Malignancies with PTEN mutations, which are associated with constitutive activation of the PI3K/Akt pathway, are relatively resistant to apoptosis and may be particularly sensitive to mTOR inhibitors. Rapamycin analogs with relatively favorable pharmaceutical properties, including CCI-779, RAD001, and AP23573, are under investigation in patients with hematologic malignancies.
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PMID:Mammalian target of rapamycin inhibition as therapy for hematologic malignancies. 1536 36

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

Neointima formation, the leading cause of restenosis, is caused by proliferation of coronary artery smooth muscle cells (CASMCs) and is associated with infiltration by monocytes. Rapamycin inhibits neointima formation after stent implantation in humans. It reduces proliferation by its effects on mammalian target of rapamycin (mTOR) kinase. In this study, we investigated the expression of mTOR in human neointima and the effect of rapamycin on global transcriptional events controlling CASMC phenotype. In neointimal CASMCs, mTOR exhibited increased phosphorylation and was translocated to the nucleus compared with control. Comparative gene expression analysis of CASMCs treated with rapamycin (100 ng/ml) revealed down-regulation of the transcription factor E2F-1, a key regulator of G(1)/S-phase entry, and of various retinoblastoma protein/E2F-1-regulated genes. In addition, we found changes in the expression of genes associated with replication, apoptosis, and extracellular matrix formation. Furthermore, rapamycin decreased the gene expression of endothelial monocyte-activating polypeptide-II (EMAP-II). This decrease of EMAP-II expression was reflected in a reduced adhesiveness of CASMCs for monocytic cells. Addition of EMAP-II counteracted the antiadhesive effect of rapamycin. Therefore, EMAP-II may comprise a mechanism of rapamycin-mediated reduction of the proinflammatory activation of CASMCs. The effects reported here of rapamycin on the down-regulation of genes involved in cell cycle progression, apoptosis, proliferation, and extracellular matrix formation in CASMCs provide an explanation of how rapamycin reduces CASMC proliferation. In addition, rapamycin may contribute to a reduction of inflammatory responses by reducing the adhesiveness of CASMC, a mechanism suggested to be mediated by the production and release of EMAP II.
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PMID:Rapamycin effects transcriptional programs in smooth muscle cells controlling proliferative and inflammatory properties. 1504 17

Cell cycle aberrations occurring at the G(1)/S checkpoint often lead to uncontrolled cell proliferation and tumor growth. We recently demonstrated that IL-1beta inhibits insulin-like growth factor (IGF)-I-induced cell proliferation by preventing cells from entering the S phase of the cell cycle, leading to G(0)/G(1) arrest. Notably, IL-1beta suppresses the ability of the IGF-I receptor tyrosine kinase to phosphorylate its major docking protein, insulin receptor substrate-1, in MCF-7 breast carcinoma cells. In this study, we extend this juxtamembrane cross-talk between cytokine and growth factor receptors to downstream cell cycle machinery. IL-1beta reduces the ability of IGF-I to activate Cdk2 and to induce E2F-1, cyclin A, and cyclin A-dependent phosphorylation of a retinoblastoma tumor suppressor substrate. Long-term activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, but not the mammalian target of rapamycin or mitogen-activated protein kinase pathways, is required for IGF-I to hyperphosphorylate retinoblastoma and to cause accumulation of E2F-1 and cyclin A. In the absence of IGF-I to induce Akt activation and cell cycle progression, IL-1beta has no effect. IL-1beta induces p21(Cip1/Waf1), which may contribute to its inhibition of IGF-I-activated Cdk2. Collectively, these data establish a novel mechanism by which prolonged Akt phosphorylation serves as a convergent target for both IGF-I and IL-1beta; stimulation by growth factors such as IGF-I promotes G(1)-S phase progression, whereas IL-1beta antagonizes IGF-I-induced Akt phosphorylation to induce cytostasis. In this manner, Akt serves as a critical bridge that links proximal receptor signaling events to more distal cell cycle machinery.
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PMID:IL-1beta suppresses prolonged Akt activation and expression of E2F-1 and cyclin A in breast cancer cells. 1518 2


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