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)

Advanced disease accounts for the majority of prostate cancer-related deaths and androgen deprivation therapy (ADT) is the standard of care for these patients. Many patients undergoing ADT become resistant to its effects and progress to castrate-resistant prostate cancer (CRPC). Current therapies for CRPC patients are inadequate, with progression-free survival rates as low as 2 months. The molecular events that promote CRPC are poorly understood. ETS (v-ets erythroblastosis virus E26 oncogene) transcription factors are regulators of carcinogenesis. Protein levels of the archetypical ETS factor, ETS1, are increased in clinical and latent prostate cancer relative to benign prostatic hyperplasia and normal prostate to promote multiple cancer-associated processes, such as energy metabolism, matrix degradation, survival, angiogenesis, migration and invasion. Our studies have found that ETS1 expression is highest in high-grade prostate cancer (Gleason 7 and above). Increased ETS1 expression and transcriptional activity promotes an aggressive and castrate-resistant phenotype in immortalized prostate cancer cells. Elevated AKT (v-akt murine thymoma viral oncogene homolog) activity was demonstrated to increase ETS1 protein levels specifically in castrate-resistant cells and exogenous ETS1 expression was sufficient to rescue invasive potential decreased by inhibition of AKT activity. Significantly, targeted androgen receptor activity altered ETS1 expression, which in turn altered the castrate-resistant phenotype. These data suggest a role for oncogenic ETS1 transcriptional activity in promoting aggressive prostate cancer and the castrate-resistant phenotype.
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PMID:ETS1 transcriptional activity is increased in advanced prostate cancer and promotes the castrate-resistant phenotype. 2223 38

Speckle-type POZ (pox virus and zinc finger protein) protein (SPOP) is an E3 ubiquitin ligase adaptor protein that is frequently mutated in prostate and endometrial cancers. All the cancer-associated SPOP mutations reported to date are clustered in the meprin and TRAF (Tumor necrosis factor receptor-associated factor) homology (MATH) domain, presumably affecting substrate binding. SPOP mutations in prostate cancer are mutually exclusive with the ETS (Erythroblast transformation-specific) family gene rearrangements and define a distinct molecular subclass of prostate cancer. SPOP mutations contribute to prostate cancer development by altering the steady-state levels of key components in the androgen-signaling pathway.
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PMID:The emerging role of speckle-type POZ protein (SPOP) in cancer development. 2505 85

Syntaxins are a conserved family of SNARE proteins and contain C-terminal transmembrane anchors required for their membrane fusion activity. Here we show that Stx3 (syntaxin 3) unexpectedly also functions as a nuclear regulator of gene expression. We found that alternative splicing creates a soluble isoform that we termed Stx3S, lacking the transmembrane anchor. Soluble Stx3S binds to the nuclear import factor RanBP5 (RAN-binding protein 5), targets to the nucleus, and interacts physically and functionally with several transcription factors, including ETV4 (ETS variant 4) and ATF2 (activating transcription factor 2). Stx3S is differentially expressed in normal human tissues, during epithelial cell polarization, and in breast cancer versus normal breast tissue. Inhibition of endogenous Stx3S expression alters the expression of cancer-associated genes and promotes cell proliferation. Similar nuclear-targeted, soluble forms of other syntaxins were identified, suggesting that nuclear signaling is a conserved, novel function common among these membrane-trafficking proteins.
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PMID:Soluble syntaxin 3 functions as a transcriptional regulator. 2947 51

Colorectal cancer (CRC) is one of the major causes of cancer-associated mortality worldwide. The currently approved therapeutic agents show a rather limited efficacy. We have recently demonstrated that the atypical cadherin FAT1 is a specific marker of CRC and that the FAT1-specific monoclonal antibody mAb198.3 may offer new therapeutic opportunities for CRC, being efficiently internalized by cancer cells and reducing cancer growth in colon cancer xenograft models. In this study we explored the therapeutic efficacy of mAb198.3 using two drug delivery systems (DDS) for improving the targeted treatment of CRC. The mAb198.3 was either directly bound to super-paramagnetic nanoparticles (spmNPs) or embedded into human erythrocyte-based magnetized carriers, named Erythro-Magneto-Hemagglutinin Virosomes (EMHVs) to produce two different novel mAb198.3 formulations. Both DDS were endowed with magnetic properties and were anchored in the target tumor site by means of an external permanent magnet. The antibody loading efficiency of these two magnetically driven drug delivery systems and the overall therapeutic efficacy of these two formulations were assessed both in vitro and in a proof-of-concept in vivo study. We demonstrated that mAb198.3 bound to spmNPs or embedded into EMHVs was very effective in targeting FAT1-positive colon cancer cells in vitro and accumulating in the tumor mass in vivo. Although both in vivo administered mAb198.3 formulations have approximately 200 lower antibody doses needed, these showed to achieve a relevant therapeutic effect, thus reducing cancer growth more efficiently respect to the naked antibody. These results indicate that the two proposed magnetically driven drug delivery systems have a considerable potential as platforms to improve bioavailability and pharmacodynamics of anti-FAT mAb198.3 and raise new opportunities for a targeted therapy of CRC.
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PMID:Magnetically driven drug delivery systems improving targeted immunotherapy for colon-rectal cancer. 2973 76

Identifying transcription factor (TF) binding to noncoding variants, uncharacterized DNA motifs, and repetitive genomic elements has been technically and computationally challenging. Current experimental methods, such as chromatin immunoprecipitation, generally test one TF at a time, and computational motif algorithms often lead to false-positive and -negative predictions. To address these limitations, we developed an experimental approach based on enhanced yeast one-hybrid assays. The first variation of this approach interrogates the binding of >1000 human TFs to repetitive DNA elements, while the second evaluates TF binding to single nucleotide variants, short insertions and deletions (indels), and novel DNA motifs. Using this approach, we detected the binding of 75 TFs, including several nuclear hormone receptors and ETS factors, to the highly repetitive Alu elements. Further, we identified cancer-associated changes in TF binding, including gain of interactions involving ETS TFs and loss of interactions involving KLF TFs to different mutations in the TERT promoter, and gain of a MYB interaction with an 18-bp indel in the TAL1 superenhancer. Additionally, we identified TFs that bind to three uncharacterized DNA motifs identified in DNase footprinting assays. We anticipate that these enhanced yeast one-hybrid approaches will expand our capabilities to study genetic variation and undercharacterized genomic regions.
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PMID:Discovering human transcription factor physical interactions with genetic variants, novel DNA motifs, and repetitive elements using enhanced yeast one-hybrid assays. 3148 62