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

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator composed of HIF-1alpha and HIF-1beta subunits. Several dozen HIF-1 targets are known, including the gene encoding vascular endothelial growth factor (VEGF). Under hypoxic conditions, HIF-1alpha expression increases as a result of decreased ubiquitination and degradation. The tumor suppressors VHL (von Hippel-Lindau protein) and p53 target HIF-1alpha for ubiquitination such that their inactivation in tumor cells increases the half-life of HIF-1alpha. Increased phosphatidylinositol 3-kinase (PI3K) and AKT or decreased PTEN activity in prostate cancer cells also increases HIF-1alpha expression by an undefined mechanism. In breast cancer, increased activity of the HER2 (also known as neu) receptor tyrosine kinase is associated with increased tumor grade, chemotherapy resistance, and decreased patient survival. HER2 has also been implicated as an inducer of VEGF expression. Here we demonstrate that HER2 signaling induced by overexpression in mouse 3T3 cells or heregulin stimulation of human MCF-7 breast cancer cells results in increased HIF-1alpha protein and VEGF mRNA expression that is dependent upon activity of PI3K, AKT (also known as protein kinase B), and the downstream kinase FRAP (FKBP-rapamycin-associated protein). In contrast to other inducers of HIF-1 expression, heregulin stimulation does not affect the half-life of HIF-1alpha but instead stimulates HIF-1alpha synthesis in a rapamycin-dependent manner. The 5'-untranslated region of HIF-1alpha mRNA directs heregulin-inducible expression of a heterologous protein. These data provide a molecular basis for VEGF induction and tumor angiogenesis by heregulin-HER2 signaling and establish a novel mechanism for the regulation of HIF-1alpha expression.
 ...
PMID:HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. 1135 7

Growing evidence indicates that inflammation is a contributing factor leading to cancer development. However, pathways involved in this progression are not well understood. To examine whether HIF-1alpha is a factor linking inflammation and tumorigenesis, we investigated whether the HIF-1 signaling pathway was stimulated by the pro-inflammatory cytokine interleukin-1beta (IL-1beta) in A549 cells. We find that IL-1beta up-regulated HIF-1alpha protein under normoxia and activated the HIF-1-responsive gene vascular endothelial growth factor (VEGF) via a pathway dependent on nuclear factor kappaB (NFkB). Interestingly, although this pathway is stimulated by upstream signaling via AKT and mTOR and requires new transcription, IL-1 mediated HIF-1alpha induction also utilizes a post-transcriptional mechanism that involves antagonism of VHL-dependent HIF-1alpha degradation, which results in increased HIF-1alpha protein stability. IL-1 mediated NFkB-dependent cyclooxygenases-2 (COX-2) expression served as a positive effector for HIF-1alpha induction. Although COX-2 inhibitors attenuated IL-1 mediated HIF-1alpha induction, prostaglandin E2 (PGE2), a physiological product of COX-2, induced HIF-1alpha protein in a dose-dependent manner. Our data, therefore, demonstrate that IL-1beta up-regulates functional HIF-1alpha protein through a classical inflammatory signaling pathway involving NFkB and COX-2, culminating in up-regulation of VEGF, a potent angiogenic factor required for tumor growth and metastasis. Thus, HIF-1 is identified as a pivotal transcription factor linking the inflammatory and oncogenic pathways.
 ...
PMID:IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. 1295 48

The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Understanding the mechanisms regulating VEGF expression in neuroblastoma cells provides additional therapeutic options to control neuroblastoma tumor growth. VEGF mRNA is controlled by growth factors and hypoxia via the transcription factor hypoxia-inducible factor (HIF-1alpha). HIF-1alpha protein levels are regulated by the von Hippel Lindau tumor suppressor gene, VHL, which targets HIF-1alpha degradation. To determine whether the levels of VEGF in neuroblastomas are due to mutations in VHL, we evaluated genomic DNA from 15 neuroblastoma cell lines using PCR. We found no mutations in exons 1, 2, or 3 of the VHL gene. VEGF mRNA levels in neuroblastoma cells cultured in serum-free medium increased after 8 to 16 hours in serum, insulin-like growth factor-I (IGF-I), epidermal growth factor, or platelet-derived growth factor. Serum/IGF-I induced increases in HIF-1alpha protein that temporally paralleled increases in VEGF mRNA, whereas HIF-1beta levels were unaffected. VEGF and HIF-1alpha levels were blocked by inhibitors of phosphatidylinositol 3-kinase and mammalian target of rapamycin. Furthermore, we confirmed that HIF-1alpha mediates approximately 40% of the growth factor activity stimulating VEGF protein expression. Topotecan blocked the IGF-I-stimulated increase in HIF-1alpha but not HIF-1beta, and this resulted in a decrease in VEGF in four neuroblastoma cell lines tested. These data indicate that growth factors in an autocrine or paracrine manner play a major role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to phosphatidylinositol 3-kinase, mammalian target of rapamycin, and/or HIF-1alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.
 ...
PMID:Topotecan blocks hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression induced by insulin-like growth factor-I in neuroblastoma cells. 1593 Feb 97

The PI3K-Akt-mTOR growth-regulating pathway is conserved from mammals to flies and hyperactivated in many cancers. Accordingly, rapamycin analogs, which are inhibitors of mTOR-Raptor signaling, have recently garnered much interest as potential therapeutic agents against cancer. However, due to the heterogeneity of tumors, prior knowledge of the genetic and biochemical background of cancer cells will be required for effective targeted therapy. Thus, the identification of biological markers against activated oncogenic pathways is needed. In the January issue of Nature Medicine, Thomas et al. identify the loss of VHL tumor suppressor gene as a potential determining factor in tumor sensitivity to rapamycin.
 ...
PMID:TORgeting oncogene addiction for cancer therapy. 1647 75

The VHL tumor-suppressor gene is mutated or silenced in most clear cell renal carcinomas (RCCs). pVHL loss results in the stabilization of the heterodimeric transcription factor hypoxia-inducible factor (HIF) and enhanced transactivation of HIF target genes. Downregulation of HIF is both necessary and sufficient for pVHL to suppress the growth of human renal carcinoma cells in preclinical models. HIF itself has been difficult to inhibit with drug-like molecules although a number of agents that indirectly inhibit HIF, including mammalian target of rapamycin (mTOR) inhibitors, have been identified. Moreover, a number of drugs have been developed that target HIF-responsive gene products, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), implicated in tumorigenesis. Many of these targeted therapies have demonstrated significant activity in kidney cancer clinical trials and represent substantive advances in the treatment of this disease. How these agents should be combined with one another and with conventional agents is the subject of current trials.
 ...
PMID:Molecular pathways in renal cell carcinoma--rationale for targeted treatment. 1704 88

The signalling components upstream and downstream of the protein kinase mammalian target of rapamycin (mTOR) are frequently altered in a wide variety of human diseases. Upstream of mTOR key signalling molecules are the small GTPase Ras, the lipid kinase PI3K, the Akt kinase, and the GTPase Rheb, which are known to be deregulated in many human cancers. Mutations in the mTOR pathway component genes TSC1, TSC2, LKB1, PTEN, VHL, NF1 and PKD1 trigger the development of the syndromes tuberous sclerosis, Peutz-Jeghers syndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease, Proteus syndrome, von Hippel-Lindau disease, Neurofibromatosis type 1, and Polycystic kidney disease, respectively. In addition, the tuberous sclerosis proteins have been implicated in the development of several sporadic tumors and in the control of the cyclin-dependent kinase inhibitor p27, known to be of relevance for several cancers. Recently, it has been recognized that mTOR is regulated by TNF-alpha and Wnt, both of which have been shown to play critical roles in the development of many human neoplasias. In addition to all these human diseases, the role of mTOR in Alzheimer's disease, cardiac hypertrophy, obesity and type 2 diabetes is discussed.
 ...
PMID:The mTOR pathway and its role in human genetic diseases. 1859 80

Malignant renal tumors constitute 3% of human cancers, although their frequency differs greatly in various areas. Since the fifties, the incidence of renal cancers has been increasing, but at the some time the prognosis has been improving. In particular, in the last years, several new treatment modalities have been introduced, relying on the understanding of renal cancer biology. The identified etiological factors include smoking, increased body mass, dietary factors and chronic renal disease. There are several renal tumor types differing in morphology, molecular genetics and biology. Inactivation of the VHL gene leads to formation of the most frequent form in adults, namely clear cell carcinoma. The VHL gene product, a component of an ubiquitin-ligase complex, regulates expression of several genes. Papillary carcinomas depend mainly on the HGF receptor gene (c-Met) activating mutations. At least two types of papillary carcinomas exist, which have different morphology and prognosis. The molecular biology of chromophobe carcinoma and oncocytoma is poorly understood. Differential diagnosis of these tumors is particularly difficult and may require extensive immunohistochemical and molecular studies. Collecting duct carcinoma and medullary carcinoma are extremely aggressive but rare tumors. Some renal tumors have been described or recognized only relatively recently; these newer entities include multilocular cystic clear cell carcinoma, spindle cell papillary mucinous carcinoma, tubulocystic carcinoma, renal epithelial and stromal tumor, epithelioid and oncocytic angiomyolipoma. Besides histological typing, the prognostic factors include tumor stage, grade and several immunohistochemical and molecular markers that are currently under elaboration. The improved prognosis in renal cancer depends on earlier detection, but also on refinement of therapeutic methods. Small tumors may currently be treated by partial nephrectomy or radiofrequency ablation and larger ones by a laparoscopic approach. All these methods seem to give satisfactory results with low morbidity and mortality rates. Renal carcinoma is notorious for its low sensitivity to chemotherapy and radiotherapy. For several years, immunological treatment with IL-2 and INF-alpha was the only adjuvant therapy method. However, recently several new drugs have been introduced; they act on tyrosine-kinase receptors, VEGF, c-Met or mTOR pathway. With this progress, perfect understanding of renal tumor biology and exact histological diagnosis have become of prime practical importance.
 ...
PMID:Pathology of renal tumors in adults. Molecular biology, histopathological diagnosis and prognosis. 1909 56

Several novel therapies have been approved recently in advanced renal cell carcinoma (RCC). These agents inhibit pathways downstream of loss of the von Hippel-Lindau gene VHL. They target the vascular endothelial growth factor (VEGF) ligand, VEGF receptor (VEGFR), mammalian target of rapamycin (mTOR), and other potentially important pathways. Even with improvements in survival, disease progresses in all patients. There is a critical need to increase complete responses (now rare). One such strategy is combining several agents to block different levels of the VEGF-VEGFR axis (vertical blockade). Alternatively, combination of a VEGF-VEGFR inhibitor with an mTOR inhibitor is attractive. Finally, horizontal blockade of VEGFR with epidermal growth factor receptor and/or platelet-derived growth factor receptor, all signaling pathways activated by hypoxia-inducible factor, is another approach. Already trials have revealed difficulties with combination therapy. By combining agents, the toxicity of 1 or both can be enhanced. The authors of this article report their experience with sorafenib plus bevacizumab, which produced increases in hand-foot syndrome, hypertension, and proteinuria, all known toxic effects. Clinical activity was impressive with 25 responses in 48 patients (52% response rate). Other combinations also required dose reductions (sorafenib with temsirolimus) or were intolerable (sunitinib with temsirolimus or sunitinib with bevacizumab). Unexpected toxicity characterized by microangiopathic hemolytic anemia occurred late in treatment with sunitinib and bevacizumab. Toxicity may be more severe in patients with RCC, who frequently have 1 kidney and poor renal function. Once tolerability for combination regimens has been established, it will be critical to design informative phase 2 trials and address the benefit of combination versus sequential therapy.
 ...
PMID:Combination targeted therapy in advanced renal cell carcinoma. 1940 58

The availability of approved agents with distinct mechanisms of action has encouraged investigations to identify optimal treatment strategies for specific patients and specific tumor features. Study of tumors from patients treated with interleukin-2 (IL-2) has suggested that response was unlikely in patients with tumors with papillary features or low carbonic anhydrase IX (CAIX) expression. A model combining histologic features and CAIX expression separated patients into 2 groups of roughly equal size, with 96% of the responding patients being in the favorable prognostic group. Additional studies have begun to identify molecular features that might predict response to IL-2 therapy. In contrast, clinical trial data suggest that temsirolimus was relatively more active than interferon in patients with tumors containing non-clear cell features. Furthermore, pathologic examination showed no correlation of response with CAIX expression, but an apparent association with high expression of either phospho-AKT or phospho-S6, proteins either upstream or downstream of mammalian target of rapamycin. Preliminary investigations of tumor specimens from patients receiving vascular endothelial growth factor-targeted therapy suggested that high hypoxia-inducible factor expression might predict response. In addition, response appeared more likely in tumors with mutated or methylated VHL genes; however, substantial antitumor activity was still observed in patients with VHL wild-type tumors, particularly in patients treated with either sunitinib or axitinib, rather than bevacizumab or sorafenib. Although these data provide some guidance in treatment selection, considerably more research is needed to identify and validate selection models for particular treatment approaches, and to enable rational and optimal utilization of the available treatment options.
 ...
PMID:Treatment selection for patients with metastatic renal cell carcinoma. 1940 69

The therapeutic options in metastatic renal cell carcinoma have been recently expanded by the discovery of the VHL gene, the mutation of which is associated with development of clear cell carcinoma, and overexpression of the angiogenesis pathway, resulting in a very vascular tumor. This breakthrough in science led to the development of a variety of small molecules inhibiting the VEGF-dependent angiogenic pathway, such as sunitinib and sorafenib. These agents prolong overall and progression-free survival, respectively. The result was the development of robust front-line therapies which ultimately fail and are associated with disease progression. In this setting, there existed an unmet need for developing second-line therapies for patients with refractory metastatic renal cell carcinoma (MRCC). Everolimus (RAD 001) is an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway. The double-blind, randomized, placebo-controlled phase III trial of everolimus (RECORD-1) conducted in MRCC patients after progression on sunitinib or sorafenib, or both, demonstrated a progression-free survival benefit favoring the study drug (4.9 months vs 1.9 months, HR 0.33, 95% CI 0.25 to 0.43, P </= 0 0.001). Everolimus thus established itself as a standard of care in the second-line setting for patients with MRCC who have failed treatment with VEGF receptor inhibitors.
 ...
PMID:Role of everolimus in the treatment of renal cell carcinoma. 1977 11


1 2 3 4 5 6 7 Next >>