Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drosophila Discs large (Dlg), Scribble (Scrib) and Lethal giant larvae (Lgl) act in concert as regulators of epithelial polarity, and human homologs of Drosophila dlg, scrib, and lgl are cancer-associated genes. LLGL1, LLGL2, and LLGL3/STXBP5 genes, encoding LGL1, LGL2, and LGL3/Tomosyn, respectively, are human homologs of Drosophila lgl gene. Here, we identified and characterized LLGL4 (also known as STXBP5L) gene encoding LGL4 protein, by using bioinformatics. Uncharacterized human KIAA1006 cDNA (AB023223) was derived from human LLGL4 gene. LLGL4 mRNA was expressed in kidney, brain hippocampus, and also in lung carcinoid, and germ cell tumors. LLGL4 gene, consisting of 28 exons, was mapped to human chromosome 3q13.33. Mouse A830015P08Rik cDNA (NM_172440.1) was a 3'-truncated partial Llgl4 cDNA. Nucleotide sequence of full-length mouse Llgl4 cDNA was determined in silico by assembling A830015P08Rik cDNA, BU609516 EST and last two exons of Llgl4 gene within mouse genome clone RP24-174G4 (AC118742.3). Human LGL4 showed 95.8% total-amino-acid identity with mouse Lgl4, and 68.4% total-amino-acid identity with human LGL3. LGLH1 domain (codon 1-11 of LGL4), LGLH2 domain (codon 52-98) and LGLH3 domain (codon 994-1054) were identified as novel conserved regions among LGL family members. LGL1 and LGL2 consist of LGLH1, LGLH2, LGLH3 domains and five WD40 repeats, while LGL3 and LGL4 consist of LGLH1, LGLH2, LGLH3 domains, five WD40 repeats and the C-terminal Syntaxin-binding SNARE domain. This is the first report on identification and characterization of human LLGL4 and mouse Llgl4 genes.
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PMID:Identification and characterization of human LLGL4 gene and mouse Llgl4 gene in silico. 1476 61

In the middle of the last century, there was a spectacular progress in the discovery, characterization and synthesis of neuropeptides. This was only possible because increasingly sophisticated analytical and isolation technology was becoming available. The pituitary lobes have become a real treasure house for the detection of different peptides, but also other glands and organs in the gastrointestinal (GI) and central nervous system (CNS) tracts have contained an ever growing list of regulatory peptides with sometimes unknown functionality. The main burning issues were to elucidate their role in physiology and, case by case and based on their structure, whether it was possible to design useful drugs for human therapy. Both issues were and are still being dealt with, and the history of somatostatin and somatostatin analogs is a good example of how such issues are being tackled successfully. In 1973, Brazeau and Guillemin's search at the Salk Institute for a GHRH in extracts of thousands of sheep hypothalami was crowned by a surprise, the discovery of a GHRH antagonist, a 14-amino acid Cystin bridge-containing peptide which they called somatostatin. This neuropetide appeared to be widely distributed in animal and human organs in the periphery and CNS, suggesting its potential regulatory functions, yet a thorough characterization of its properties due to its extremely short half-life was not possible. More insight could only be feasible with the synthesis of stable and potent analogs, a program that soon started in different research centers around the world. After having elucidated the 3-dimensional structure, the enzymatic degradation pattern and minimal chain length for biological activity of the natural hormone, the synthesis of a large number of analogs was started as early as 1974. The approach of the Sandoz team was to start with a hexapeptide lead structure Cys-Phe-DTrp-Lys-Thr-Cys and, by systematic elongation of the N and C terminals, in 1980 they managed to characterize the most stable and active analog with the following structure: H-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-OI-Octreotide. It was more potent in inhibiting GH in vivo compared to the native hormone. It demonstrated sufficient stability in vivo and, therefore, it was selected for clinical studies. In 1988, the first registration was obtained for treating acromegaly and carcinoid tumors. Since then, different depot preparations have been made available. Other analogs with similar structures have been also synthesized and are commercially available. The so-called targeting approach takes advantage of the presence of somatostatin receptors on different tumors. By coupling octreotide structural elements to so-called cage molecules complexing B or Y emitting isotopes, also the detection of somatostatin receptor containing tumors could be visualized and treated. The use of different somatostatin derivatives found its way since then both in basic research and in human therapy, and it is still opening new and exciting prospects.
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PMID:The history of somatostatin analogs. 1662 37

Hallmark deregulated signaling in cancer cells drives excessive ribosome biogenesis within the nucleolus, which elicits unbridled cell growth and proliferation. The rate-limiting step of ribosome biogenesis is synthesis of rRNA (building blocks of ribosomes) by RNA Polymerase I (Pol I). Numerous kinase pathways and products of proto-oncogenes can up-regulate Pol I, whereas tumor suppressor proteins can inhibit rRNA synthesis. In tumorigenesis, activating mutations in certain cancer-associated kinases and loss-of-function mutations in tumor suppressors lead to deregulated signaling that stimulates Pol I transcription with resultant increases in ribosome biogenesis, protein synthesis, cell growth, and proliferation. Certain anticancer therapeutics, such as cisplatin and 5-fluorouracil, reportedly exert, at least partially, their activity through disruption of ribosome biogenesis, yet many prime targets for anticancer drugs within the ribosome synthetic machinery of the nucleolus remain largely unexploited. Herein, we describe CX-3543, a small molecule nucleolus-targeting agent that selectively disrupts nucleolin/rDNA G-quadruplex complexes in the nucleolus, thereby inhibiting Pol I transcription and inducing apoptosis in cancer cells. CX-3543 is the first G-quadruplex interactive agent to enter human clinical trials, and it is currently under evaluation against carcinoid/neuroendocrine tumors in a phase II clinical trial.
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PMID:Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis. 1973 48

Up-regulation of phosphatidylinositol-3-kinase (PI3K)-AKT signaling facilitates tumor cell growth and inhibits cell demise. The AKT-pathway also plays an important role in cytostatic therapy resistance and response to hypoxia and angiogenesis. Using real-time cell proliferation assay we examined the potency of triciribine in three distinct neuroendocrine gastrointestinal tumor cell lines. Also we investigated triciribine's induction of apoptosis and effects on a broad range of cancer-associated gene products. Furthermore, we characterized the role of PTEN as a possible predictor of sensitivity to triciribine in GEP-NETs. We also looked for additive anti-neoplastic effects of triciribine when combined with conventional cytostatic drugs or other targeted drugs, affecting different molecules of the PI3K-AKT-pathway and we assessed the potency of triciribine to inhibit tumor growth in vivo, by using the chick chorioallantoic membrane assay. Treatment of insulinoma (CM) or gut neuroendocrine tumor cells (STC-1) with triciribine significantly reduced tumor cell growth by 59% and 65%, respectively. By contrast, the highly expressing PTEN carcinoid cell line BON did not respond, even at higher doses. Combinations of triciribine with classic cytostatic drugs as well as drugs targeting other molecules of the PI3K-AKT-pathway led to synergistic anti-proliferative effects. Additional in vivo-evaluations confirmed the anti-neoplastic potency of triciribine. Thus, our data show that inhibition the AKT-pathway potently reduces the growth of GEP-NET cells alone or in combination therapies. AKT inhibition may provide a rationale for future evaluations.
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PMID:AKT inhibition by triciribine alone or as combination therapy for growth control of gastroenteropancreatic neuroendocrine tumors. 2207 56