• ERK5 Signalling and Resistance to ERK1/2 Pathway Therapeutics: The Path Less Travelled? (babraham.ac.uk)
  • The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is frequently de-regulated in human cancer. (babraham.ac.uk)
  • However, recent studies have suggested that BRAFi/MEKi and ERK1/2i resistance can arise through activation of a parallel signalling pathway leading to activation of ERK5, an unusual protein kinase that contains both a kinase domain and a transcriptional transactivation domain. (babraham.ac.uk)
  • The canonical TGFβ signalling pathway involves ligand-dependent assembly of a heteromeric receptor complex, receptor-kinase activation and subsequent phosphorylation and activation of SMAD proteins, which are transcriptional regulators that consequently accumulate in the nucleus. (nature.com)
  • Such continuous sensing of signal intensity might involve cycling of receptors through the endocytic pathway. (nature.com)
  • An in-depth understanding of the pleiotropic cellular functions that can be evoked by TGFβ superfamily signalling will depend on a more quantitative knowledge of temporal and spatial characteristics of the pathway. (nature.com)
  • The presence of the non-canonical start codon suggests possible increased regulation of C16orf82 translation and/or possibly could allow for the translation of protein products that start with leucine instead of methionine as seen in proteins coded for by some genes present in the major histocompatibility complex. (wikipedia.org)
  • The secondary structure of the human C16orf82 protein has been predicted to be largely disordered by a number of modeling programs. (wikipedia.org)
  • Many AARS have been linked to human diseases caused not by defects in protein assembly but by these other non-canonical functions. (fascea.pics)
  • We found that the use of engineered pegRNA (epegRNA), along with the combination of introducing a V223A mutation into the M-MLV RT and updating the architecture of the PE protein by varying the SpCas9 activity and nuclear localization signals (NLSs), synergistically and significantly increased the efficiency of prime editing in wheat. (biomedcentral.com)
  • We are studying the effects and consequences of protein fusion on the transcriptional and transforming activities of these proteins using in vitro and animal models. (stanford.edu)
  • Ligands of the transforming growth factor-β (TGFβ) superfamily of growth factors initiate signal transduction through a bewildering complexity of ligand-receptor interactions. (nature.com)
  • Current projects are focused on CA and capsid interactions, proteins involved in trafficking and nuclear import, retroviral intasome structure, and analyses of the HIV-1 pre-integration complex. (pitt.edu)
  • Human intronless genes represent a unique subset of the genome that are often involved in signaling, sperm formation, immune responses, or development. (wikipedia.org)
  • Close transposon relatives and other recombination enzymes, including retroviral integrases, have served as useful models to infer functional information relevant to SB. (encyclopedia.pub)
  • Retroviral particles must bind specifically to their target cells, cross the plasma membrane, reverse-transcribe their RNA genome, while uncoating the cores, find their way to the nuclear membrane and penetrate into the nucleus to finally dock and integrate into the cellular genome. (biomedcentral.com)
  • Furthermore, GSOs protected cells against GLU-induced apoptosis by reducing the expression of the mitochondrial apoptosis-associated Bcl-2 family effector proteins and protected cells from GLU-induced oxidative damage by increasing the nuclear translocation of Nrf2 and HO-1 expression. (sdbonline.org)
  • Much has been learned regarding nuclear entry, but the cellular proteins involved are still unknown and the exact role of each viral component remains controversial [ 7 ]. (biomedcentral.com)
  • Thus, SMADs both transmit the signal into the nucleus and execute the downstream effects by directly regulating target-gene transcription. (nature.com)
  • Here, we characterize the evolution and function of the SPATA31 gene family (former designation FAM75A ), which was previously shown to be among the gene families with the strongest signal of positive selection in hominoids. (biomedcentral.com)
  • The protease not only releases small peptides, such as the amyloid-β peptide, which drives Alzheimer's disease pathogenesis, but also intracellular domains, which can have critical functions in nuclear signaling. (cipsm.de)
  • Then, beginning in the 1990s, Schimmel and others began to discover non-canonical functions in higher eukaryotes, beginning with unexpected roles in angiogenesis. (fascea.pics)
  • Signalling then converges to nuclear accumulation of transcriptionally active SMAD complexes and gives rise to a plethora of specific functional responses in both embryos and adult organisms. (nature.com)
  • An equally important challenge is understanding the functional role of signal strength and duration. (nature.com)
  • During the long journey from the cell surface to the nucleus, retroviruses will face multiple obstacles, since in addition to finding a path through the cytoplasm to the nucleus they have to cross two main barriers, the plasma and nuclear membranes, whilst at the same time avoiding or counteracting cellular defences that can interfere with many of these steps. (biomedcentral.com)
  • These resistance mechanisms frequently involve reinstatement of ERK1/2 signalling and BRAFi are now deployed in combination with one of three approved MEK1/2 inhibitors (MEKi) to provide more durable, but still transient, clinical responses. (babraham.ac.uk)
  • These findings define a molecular mechanism underlying a tumor-promoting function of thymosin β4 through activation of MRTF/SRF signaling. (aacrjournals.org)
  • In addition, nuclear accumulation of active nuclear SMAD complexes is dynamically maintained in strict accordance with the degree of receptor activation at any time of signalling. (nature.com)
  • We use molecular biology, proteomics, mouse modeling, including patient derived xenografts, and human tissues to understand how tumors that are initially responsive to therapy become resistant over time. (wisc.edu)
  • In the Wheeler lab, we use state of the art molecular biology, proteomics and mouse modeling to understand how tumors become resistant to cancer drugs. (wisc.edu)
  • A bipartite nuclear localization signal can be found starting at Arg107. (wikipedia.org)
  • After acute injury in muscle of both mouse and the fruit fly Drosophila melanogaster (used as alternative in vivo model) this study found that RACK1 accumulated in regenerating fibers while it declined with the progression of repair process. (sdbonline.org)
  • Signal duration and signal magnitude are relayed faithfully into the nucleus in a quantitative manner. (nature.com)
  • 3) We are defining the properties of cancer stem cells that initiate and sustain the unique disease features of acute leukemias through the use of various adoptive animal models. (stanford.edu)
  • The solutions obtained from VQE exhibit a high approximation ratio behavior, and consistently outperform several common portfolio models in backtesting over a long period of time. (academ.us)
  • the ascomycete trichoderma reesei is an industrial producer of cellulolytic and hemicellulolytic enzymes, and serves as a prime model for their genetic regulation. (liverpool.ac.uk)
  • Figure 3: Schematic representation of dynamic signal interpretation by SMADs. (nature.com)
  • the ß-importin kap8 (pse1/kap121) is required for nuclear import of the cellulase transcriptional regulator xyr1, asexual sporulation and stress resistance in trichoderma reesei. (liverpool.ac.uk)
  • June 18, 2010, Essentials of Trademarks P suas base for Mr. The development fact' of nuclear weapons does that they appreciate never complete Cold comprehensive P5+1. (shenservice.com)
  • and non-LTR retrotransposons, including long interspersed nuclear elements (LINEs, such as the L1 element [ 7 ] ) and short interspersed nuclear elements (SINEs, such as the Alu element [ 8 ] ). (encyclopedia.pub)
  • Here, we investigate amplification events that underlie resistance to the MEK inhibitor selumetinib (AZD6244/ARRY-142886) in COLO205 cells, a well-characterized model for reproducible emergence of drug resistance, and show that amplifications acquired are the primary cause of resistance. (babraham.ac.uk)
  • In 2008 our lab was the first to report that tumor cells that acquired resistance to cetuximab exhibited dramatic up regulation of the EGFR, secondary to loss of ubiquitination, which led to enhanced signals to other EGFR family members (HER and HER3) that promoted proliferation and survival. (wisc.edu)
  • The results showed that subcellular localization of this protein is also restricted to the nucleus and is present in all latently infected B cells with an intact EBV episome. (medscape.com)
  • Androgen receptor (AR), a transcription factor part of the nuclear receptor family, is the primary effector of testosterone and activates genes involved in growth, metabolism, and pro-survival signaling [ 6 ]. (ijbs.com)
  • In using Fyn kinase as a model, it is apparent that the Src homology 2 (SH2) and SH3 domains are necessary, however, the SH2 domain is sufficient for nuclear import due to a putative bipartite nuclear localization sequence in the SH2 domain. (umaryland.edu)
  • For example, they all form a complex with RBP-Jκ, a major Notch signaling modulator and a sequence-specific DNA-binding transcription factor that specifically upregulates EBNA-2-mediated transcriptional activation of several viral ( LMP-1/-2 ) or cellular ( CD23 ) genes. (medscape.com)
  • In unstimulated cells, p50/p65 is retained by the inhibitor IκBα in the cytoplasm that masks the p65-nuclear localization sequence (NLS). (bvsalud.org)
  • Indeed, excluding chemotherapy and immunotherapy, therapies for advanced PCa all center on blocking or interrupting AR-dependent signaling pathways. (ijbs.com)
  • In addition to its direct inhibition of Nrf2, GSK3 β also indirectly mediates the nuclear export and degradation of Nrf2 by triggering the nuclear translocation of the Src-A subfamily kinase members Src, Fyn, Yes, and Fgr. (umaryland.edu)
  • This manuscript provides a robust analysis of the regulation of nuclear import and the chromatin-binding features of AR-V7 versus AR. (elifesciences.org)
  • Our results indicate GTPase regulation at a novel point in Wg/Wnt signal transduction, and provide new insight into the categorization of ECT2 as a human proto-oncogene. (silverchair.com)
  • Androgen receptor (AR) remains a critical therapeutic target in the treatment of metastatic castration-resistant prostate cancer (CRPC), due to overactive AR signaling ( Feldman and Feldman, 2001 ). (elifesciences.org)
  • Specifically highlighted is the biology of androgen receptor (AR), the nuclear receptor transcription factor largely responsible for androgen-stimulated and castrate-recurrent (CR) PCa. (ijbs.com)
  • Current PCa treatment paradigms can be classified into three distinct but interrelated categories: targeting AR at pre-receptor, receptor, or post-receptor signaling. (ijbs.com)
  • Nuclear translocation of the p50/p65 heterodimer is essential for NF-κB signaling. (bvsalud.org)
  • [ 19 ] EBNA-3 proteins possess a number of similar structural motifs, which include a binding site for a Notch signaling mediator and a highly potent transcriptional regulator RBP-Jκ, a leucine zipper motif, an acidic domain, proline- and glutamine-rich repeats and several arginine and lysine residues known to be important for nuclear localization. (medscape.com)
  • The work reveals that AR-V7 exhibits fast nuclear import kinetics in an NLS- and importin-α/β- independent manner, dependent on the dimerization (D-box) domain mediates AR-V7 nuclear import, revealing a new function for this domain versus its role in the full-length AR. (elifesciences.org)
  • Human intronless genes represent a unique subset of the genome that are often involved in signaling, sperm formation, immune responses, or development. (wikipedia.org)
  • [ 15 , 16 ] The EBNA-3 nuclear proteins, which include EBNA-3A, -3B and -3C, are encoded by three tandemly arranged genes in the viral episome, each containing a short 5' and long 3' exon. (medscape.com)
  • Epistasis experiments from many laboratories have used these phenotypes to identify genes required for proper Wg signaling. (silverchair.com)
  • Consequently, it is surmised that Hh influences cell polarity indirectly, possibly by inducing other signaling factors (Struhl, 1997b). (sdbonline.org)
  • Wingless (Wg)/Wnt signaling is essential for patterning invertebrate and vertebrate embryos, and inappropriate Wnt activity is associated with a variety of human cancers. (silverchair.com)
  • Mutations that result in excess Wnt signaling are associated with a number of human cancers especially colorectal cancer ( Polakis, 2007 ). (silverchair.com)
  • This suggests that a second signal, received from adjacent cells, is required for entering a furrow fate and differentiating normally. (sdbonline.org)
  • However, in the quiescent stem cell niche of the adult hair follicle, LEF1-TCF Wnt reporter (TOPGAL) activity has not been observed7,8 , suggesting that if Wnt-β-catenin signalling is required universally to maintain stem cells, it acts through promoting activation rather than viability. (docksci.com)
  • In vivo transcriptional governance of hair follicle stem cells by canonical Wnt regulators. (docksci.com)
  • In vivo transcriptional governance of hair follicle stem cells by canonical Wnt regulators Wen-Hui Lien1,5 , Lisa Polak1 , Mingyan Lin2 , Kenneth Lay1 , Deyou Zheng2,3,4 and Elaine Fuchs1,6 Hair follicle stem cells (HFSCs) regenerate hair in response to Wnt signalling. (docksci.com)
  • Using a patient-derived xenograft model, we demonstrate that treatment with the cIAP1/2 inhibitor, birinapant, during the MRD phase delays the onset of resistance to BRAF inhibitor and MEK inhibitor combination therapy. (bvsalud.org)
  • Besides this canonical function, HO-1 is involved in manifestation of cancer hallmarks. (jcpjournal.org)
  • A second paper (Struhl, 1997b) deals directly with the instances in which cell polarity does not correspond to the presumed concentration gradient of Hh and considers whether Hh acts directly or by a signal relay mechanism. (sdbonline.org)
  • How might Hh polarize cells via a signal-relay mechanism? (sdbonline.org)
  • This commentary summarizes the non-canonical functions of HO-1 in the context of cancer growth and progression and underlying regulatory mechanisms. (jcpjournal.org)
  • Cytokines secreted by the cells are the key components of signaling the message of danger and defense to the cells of immune system. (mdpi.com)
  • Here, we leveraged ARID1B+/- Coffin-Siris patient-derived iPSCs and modeled cranial neural crest cell (CNCC) formation. (bvsalud.org)
  • Here, we report that AR-V7 has unique biological features that functionally differentiate it from canonical AR-fl or from the second most prevalent variant, AR-v567. (elifesciences.org)
  • Unlike the autosomes, Xi lacks TADs and compartments but instead has a unique bipartite 'megadomain' structure separated by a tandem macrosatellite repeat, Dxz4 / DXZ4 (refs. (nature.com)
  • Our studies unveil TCF3/4-TLE histone deacetylases as a repressive rheostat, whose action can be relieved by Wnt-β-catenin signalling. (docksci.com)
  • We propose that importin α3 discriminates between the transcriptionally active p50/p65 heterodimer and p50/p50 and p65/65 homodimers, ensuring fidelity in NF-κB signaling. (bvsalud.org)