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)

There is an increasing rationale for effective combinations of endocrine therapy with novel drugs that target aberrant signal transduction pathways in estrogen receptor (ER) positive breast cancer. Prolonged endocrine therapy can be associated with an acquired increase in peptide growth factor signaling (EGFR, HER2), together with cross-talk activation of ER-dependent gene transcription and cell growth that leads to endocrine resistance. Current approaches to target these pathways include both the selective ER downregulator fulvestrant, and various signal transduction inhibitors (STIs). Fulvestrant can overcome resistance to tamoxifen (TAM-R) and long-term estrogen deprivation (LTED-R) in experimental models by reducing ER expression, and represents a current option for post-menopausal women with endocrine resistant ER+ve breast cancer. Emerging data suggest that fulvestrant's effect may be greater when combined with estrogen deprivation, and several phase III trials are assessing fulvestrant combined with aromatase inhibitors (AIs). Small molecule STIs such as tyrosine kinase inhibitors (TKIs), farnesyltransferase inhibitors (FTIs) and mTOR antagonists are also active in breast cancer. Pre-clinical data suggest that combined endocrine/STI therapy may result in greater growth inhibition than either therapy alone, and thus delay emergence of resistance. Several clinical trials are now examining STIs combined with AIs both in the tamoxifen-resistant and first-line advanced breast cancer setting, while pre-surgical studies are investigating the efficacy of combined endocrine/STI therapy utilising biological primary endpoints. This article reviews the pre-clinical rationale for this strategy and the clinical trials in this area.
J Steroid Biochem Mol Biol 2005 May
PMID:Aromatase inhibitors: combinations with fulvestrant or signal transduction inhibitors as a strategy to overcome endocrine resistance. 1599 63

Rapamycin, a valuable drug with diverse clinical applications, inhibits mTOR (mammalian target of rapamycin), which is a protein kinase that controls cell growth by regulating many cellular processes, including protein synthesis and autophagy. The sensitivity of select tumor cells to rapamycin has ignited considerable excitement over its potential as an anti-cancer therapeutic. Recent findings identified a rapamycin-insensitive function of mTOR in regulating a cell-survival pathway that is hyperactive in many cancers, particularly those with elevated PtdIns3K signaling or harboring mutations in the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10). These new findings suggest that targeting this function of mTOR might have broader applications in cancer therapy. In this article, we re-evaluate mTOR signaling, suggesting a more central role for mTOR in cancers with defective PtdIns3K-PTEN signaling and conceptually discuss these implications in the context of drug discovery.
Trends Mol Med 2005 Aug
PMID:An expanding role for mTOR in cancer. 1600 36

IGF-I acutely stimulates protein synthesis in cardiac muscle through acceleration of mRNA translation. In the present study, we examined the regulatory signaling pathways and translation protein factors that potentially contribute to the myocardial responsiveness of protein synthesis to IGF-I in vivo. IGF-I was injected IV into rats and 20 min later the hearts were excised and homogenized for assay of regulatory proteins. IGF-I increased assembly of the translationally active eukaryotic initiation factor (eIF)4G.eIF4E complex. The increased assembly of eIF4G.eIF4E was associated with an enhanced eIF4G phosphorylation and increased availability of eIF4E. Increased availability of eIF4E occurred as a consequence of diminished abundance of the inactive 4E-BP1.eIF4E complex following IGF-I. The assembly of the 4E-BP1.eIF4E complex appeared to be decreased through an IGF-I-induced phosphorylation of 4E-BP1. IGF-I also caused an increase in the phosphorylation of S6K1. Activation of the potential upstream regulators of 4E-BP1 and S6K1 phosphorylation via PKB and mTOR was also observed. In contrast, there was no effect of IGF-I on phosphorylation of elongation factor (eFE)2. The results suggest the major impact of IGF-I in cardiac muscle occurred via stimulation of translation initiation rather than elongation. Furthermore, the results are consistent with a role for assembly of active eIF4G.eIF4E complex and activation of S6K1 in mediating the stimulation of mRNA translation initiation by IGF-I through a PKB/mTOR signaling pathway.
Mol Cell Biochem 2005 Apr
PMID:IGF-I activates the eIF4F system in cardiac muscle in vivo. 1601 Sep 89

There is much interest in precise functions of amino acids on mammalian growth and development. Some of amino acids play important roles in the control of gene expression by controlling the initiation phase of mRNA translation. The signal induced by leucine or arginine may stimulate cell growth. On the other hand, the other signal induced by glutamine may stimulate cellular proliferation and increase cell number, but inhibit the growth of cell size. However, there was no clear evidence that an individual amino acid specifically works as a signaling molecule. In our recent study, not only leucine, but also arginine is shown to activate the mTOR signaling pathway in rat intestinal epithelial cells. Furthermore, regarding L-Glutamine, an important amino acid that is required for culturing of numerous cell types, including rat intestinal epithelial cells, we have shown that it had an inhibitory effect on leucine- or arginine-induced activation of the mTOR signaling pathway. We have demonstrated that L-Glutamine inhibited the activation of p70 S6 kinase and phosphorylation of 4E-BP1 induced by arginine or leucine in rat intestinal epithelial cells. Based on these results, we are planning to confirm the effect of each amino acid including glutamine in an in vivo model using new born mice.
Int J Mol Med 2005 Aug
PMID:Rational role of amino acids in intestinal epithelial cells (Review). 1601 50

Breast tumors in women can adapt to endocrine deprivation therapy by developing hypersensitivity to estradiol. For this reason, aromatase inhibitors can be effective in women relapsing after treatment with tamoxifen or following oophorectomy. To understand the mechanisms responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided in vitro and in vivo evidence that long-term estradiol deprivation (LTED) causes "adaptive hypersensitivity". The primary mechanisms responsible involve up-regulation of ER alpha as well as the MAP kinase, PI-3 kinase, and mTOR growth factor pathways. ER alpha is 4-10-fold up-regulated and co-opts a classical growth factor pathway using Shc, Grb2, and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. Estradiol binds to cell membrane associated ER alpha, physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb2 and Sos which result in the rapid activation of MAP kinase. These non-genomic effects of estradiol produce biologic effects as evidenced by Elk activation and by morphologic changes in cell membranes. Additional effects include activation of PI-3 kinase and mTOR pathways through estradiol induced binding of ER alpha to the IGF-1 and EGF receptors. Further proof of the non-genomic effects of estradiol involved use of "designer" cells which selectively express ER alpha in nucleus, cytosol, and cell membrane. We have used a new downstream inhibitor of these pathways, farnesyl-thio-salicylic acid (FTS), to block proliferation in hypersensitive cells as a model for a potentially effective strategy for treatment of patients.
J Steroid Biochem Mol Biol 2005 May
PMID:Adaptive hypersensitivity to estrogen: mechanisms and clinical relevance to aromatase inhibitor therapy in breast cancer treatment. 1602 45

PTEN is a tumor suppressor whose function is frequently lost in human cancer. It possesses a lipid phosphatase activity that represses the activation of PI3 kinase/Akt signaling, leading to decreased cell growth, proliferation, and survival. The potential for PTEN to regulate transcription of the large rRNAs by RNA polymerase I (RNA Pol I) was investigated. As increased synthesis of rRNAs is a hallmark of neoplastic transformation, the ability of PTEN to control the transcription of rRNAs might be crucial for its tumor suppressor function. The expression of PTEN in PTEN-deficient cells represses RNA Pol I transcription, while decreasing PTEN expression enhances transcription. PTEN-mediated repression requires its lipid phosphatase activity and is independent of the p53 status of the cell. This event can be uncoupled from PTEN's ability to regulate the cell cycle. RNA Pol I is regulated through PI3 kinase/Akt/mammalian target of rapamycin/S6 kinase, and the expression of constitutively activated S6 kinase is able to abrogate transcription repression by PTEN. No change in the expression of the RNA Pol I transcription components, upstream binding factor or SL1, was observed upon PTEN expression. However, chromatin immunoprecipitation assays demonstrate that PTEN differentially reduces the occupancy of the SL1 subunits on the rRNA gene promoter. Furthermore, PTEN induces dissociation of the SL1 subunits. Together, these results demonstrate that PTEN represses RNA Pol I transcription through a novel mechanism that involves disruption of the SL1 complex.
Mol Cell Biol 2005 Aug
PMID:PTEN represses RNA Polymerase I transcription by disrupting the SL1 complex. 1605 4

Overexpression of human IGF-1 with the bovine keratin 5 (BK5) promoter (BK5.IGF-1 transgenic mice) induces persistent epidermal hyperplasia and leads to spontaneous skin tumor formation. In previous work, PI3K and Akt activities were found to be elevated in the epidermis of BK5.IGF-1 transgenic mice compared to nontransgenic littermates. In the present study, we examined the importance of the PI3K/Akt signaling pathway in mediating the skin phenotype and the skin tumor promoting action of IGF-1 in these mice. Western blot analyses with epidermal lysates showed that signaling components downstream of PI3K/Akt were altered in epidermis of BK5.IGF-1 mice. Increased phosphorylation of GSK-3 (Ser(9/21)), TSC2(Thr(1462)), and mTOR(Ser(2448)) was observed. In addition, hypophosphorylation and increased protein levels of beta-catenin were observed in the epidermis of BK5.IGF-1 mice. These data suggested that components downstream of Akt might be affected, including cell cycle machinery in the epidermis of BK5.IGF-1 mice. Protein levels of cyclins (D1, E, A), E2F1, and E2F4 were all elevated in the epidermis of BK5.IGF-1 mice. Also, immunoprecipitation experiments demonstrated an increase in cdk4/cyclin D1 and cdk2/cyclin E complex formation, suggesting increased cdk activity in the epidermis of transgenic mice. In further studies, the PI3K inhibitor, LY294002, significantly blocked IGF-1-mediated epidermal proliferation and skin tumor promotion in DMBA-initiated BK5.IGF-1 mice. In addition, inhibition of PI3K/Akt with LY294002 reversed many of the cell cycle related changes observed in untreated transgenic animals. Collectively, the current results supported the hypothesis that elevated PI3K/Akt activity and subsequent activation of one or more downstream effector pathways contributed significantly to the tumor promoting action of IGF-1 in the epidermis of BK5.IGF-1 mice.
Mol Carcinog 2005 Oct
PMID:Role of PI3K/Akt signaling in insulin-like growth factor-1 (IGF-1) skin tumor promotion. 1608 73

Mutations of the thyroid hormone receptor beta (TRbeta) gene cause resistance to thyroid hormone (RTH). RTH is characterized by increased serum thyroid hormone associated with nonsuppressible thyroid-stimulating hormone (TSH) and impaired growth. It is unclear how the actions of TRbeta mutants are modulated in vivo to affect the manifestation of RTH. Using a mouse model of RTH that harbors a knockin mutation of the TRbeta gene (TRbetaPV mouse), we investigated the effect of the steroid hormone receptor coactivator 3 (SRC-3) on RTH. In TRbetaPV mice deficient in SRC-3, dysfunction of the pituitary-thyroid axis and hypercholesterolemia was lessened, but growth impairment of RTH was worsened. The lessened dysfunction of the pituitary-thyroid axis was attributed to a significant decrease in growth of the thyroid and pituitary. Serum insulin-like growth factor 1 (IGF-1) was further reduced in TRbetaPV mice deficient in SRC-3. This effect led to reduced signaling of the IGF-1/phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway that is known to mediate cell growth and proliferation. Thus, SRC-3 modulates RTH by at least two mechanisms, one via its role as a receptor coregulator and the other via its growth regulatory role through the IGF-1/PI3K/AKT/mTOR signaling.
Mol Cell Biol 2005 Sep
PMID:Dual functions of the steroid hormone receptor coactivator 3 in modulating resistance to thyroid hormone. 1610 15

Estrogens, which have been strongly implicated in the development of breast cancer, enhance proliferation of mammary epithelial cells and, importantly, estrogen receptor (ER)-positive breast cancer cells. In the absence of serum growth factors, the ER-positive MCF-7 breast cancer cell line undergoes apoptosis. Estrogens, most commonly 17-beta-estradiol (E2), can suppress apoptosis in MCF-7 cells deprived of serum. While E2 stimulated a short-term transient increase in Myc expression, E2 stimulated a sustained increase in Myc expression that was detectable at 48 h and pronounced at 5 days, the point where increased proliferation of MCF-7 cells in the absence of serum could be detected. The delayed increase in Myc expression was not dependent upon transcription of the Myc gene. Suppression of Myc expression reversed the survival effects of E2. The Myc-dependent survival signal generated by E2 was dependent upon basal levels of mTOR (mammalian target of rapamycin) and two upstream regulators of mTOR, phosphatidylinositol 3-kinase and phospholipase D (PLD). Stable elevated expression of PLD2 also increased Myc expression and provided a Myc-dependent survival signal in the absence of E2. These data provide evidence that E2 promotes survival signals in breast cancer cells through an mTOR-dependent increase in Myc expression. The data also suggest that elevated PLD expression, which is common in breast cancer, confers E2 independence.
Mol Cell Biol 2005 Sep
PMID:Survival signals generated by estrogen and phospholipase D in MCF-7 breast cancer cells are dependent on Myc. 1610 34

Like many tumors, malignant mesothelioma exhibits significant chemoresistance and resistance to apoptosis in vivo that is not seen in current in vitro models. To study the mechanisms of this multicellular resistance, biologically relevant in vitro models are necessary. Therefore, we characterized and tested human mesothelioma tissue grown in vitro as tumor fragment spheroids. After 5-10 d in culture, fragments from each of 15 human mesothelioma tumors rounded into spheroids. The tumor fragment spheroids maintained multiple characteristics of the original tumors for up to 3 mo including the presence of viable mesothelioma cells, macrophages, and a collagen-rich stroma. In 14-d-old spheroids, mesothelioma cells showed the same proliferation rate and expression of a death receptor, DR5, as in the original tumor. To determine responses to treatment, we treated tumor fragment spheroids grown from three separate tumors with agents, TNF-related apoptosis-inducing ligand (TRAIL) plus cycloheximide, that induced near total apoptosis in three human mesothelioma cell lines (M28, REN, MS-1) grown as monolayers (94 +/- 6% apoptosis; mean +/- SEM). Compared with mesothelioma cells in monolayers, mesothelioma cells in the spheroids were resistant to TRAIL plus cycloheximide (32 +/- 4% apoptosis; mean +/- SEM). Apoptotic resistance of mesothelioma cells was significantly reduced by inhibiting either the PI3K/Akt pathway with LY294002 (47 +/- 6% apoptosis) or the mTOR pathway with rapamycin (50 +/- 17% apoptosis). We conclude that human mesothelioma can be maintained in vitro in a biologically relevant model that exhibits apoptotic resistance, thereby permitting study of its tumor biology and of novel approaches to therapy.
Am J Respir Cell Mol Biol 2005 Dec
PMID:A novel in vitro model of human mesothelioma for studying tumor biology and apoptotic resistance. 1612 94


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