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Achaete Scute Complex

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Herbert Chen – One of the best experts on this subject based on the ideXlab platform.

  • chrysin suppresses Achaete Scute Complex like 1 and alters the neuroendocrine phenotype of carcinoids
    Cancer Gene Therapy, 2015
    Co-Authors: Yash R Somnay, Herbert Chen, Barbara Zarebczan Dull, Jacob Eide, Renata Jaskulasztul
    Abstract:

    Carcinoids are neuroendocrine neoplasms that cause significant morbidity and mortality and for which few effective therapies are available. Given the recent identification of the anticancer flavonoid chrysin, we sought to investigate its therapeutic potential in carcinoids. Here we report chrysin’s ability to modulate the AchaeteScute Complex-like 1 (ASCL1), a neuroendocrine-specific transcription factor highly implicated in the malignant phenotype of carcinoids and other neuroendocrine cancers. Moreover, we elucidate the role of ASCL1 in carcinoid growth and bioactivity. Treatment of two carcinoid cell lines (BON and H727) with varying chrysin concentrations suppressed cell proliferation, while reducing expression of ASCL1 and the neuroendocrine biomarker chromogranin A (CgA), demonstrated by western blotting. Propidium iodide and phycoerythrin AnnexinV/7-aminoactinomycin D staining and sorting following chrysin treatment revealed S/G2 phase arrest and apoptosis, respectively. This was corroborated by chrysin-induced cleavage of caspase-3 and poly ADP-ribose polymerase and activation of p21Waf1/Cip1. Furthermore, direct ASCL1 knockdown with an ASCL1-specific small interfering RNA inhibited CgA and synaptophysin expression as well as carcinoid proliferation, while also reducing cyclin B1 and D1 and increasing p21Waf1/Cip1 and p27Kip1 expression, suggesting an arrest of the cell cycle. Collectively, these findings warrant the deliberation of targeted ASCL1 suppression by chrysin or other agents as a therapeutic approach for carcinoid management.

  • Hesperetin, a potential therapy for carcinoid cancer.
    American journal of surgery, 2011
    Co-Authors: Barbara Zarebczan, Muthusamy Kunnimalaiyaan, Scott N. Pinchot, Herbert Chen
    Abstract:

    Abstract Background The investigators’ laboratory has demonstrated that the Notch1 signaling pathway acts as a tumor suppressor in carcinoid tumors. The aim of this study was to examine hesperetin, a flavonoid, as a potential Notch1 activator and carcinoid tumor suppressor. Methods A high-throughput drug screen revealed hesperetin as a Notch1 activator. Human gastrointestinal carcinoid (BON) cell growth after hesperetin treatment was assessed with a 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide assay. Western blots were used to measure neuroendocrine tumor markers, human AchaeteScute Complex-like 1, and chromogranin A. Notch1 expression was measured using western blot analysis and real-time polymerase chain reaction. Results Hesperetin induced cell death in a dose-dependent manner and reduced AchaeteScute Complex-like 1 and chromogranin A expression, with a concomitant rise in Notch1 levels. It also induced Notch1 messenger ribonucleic acid, indicating regulation at the transcriptional level. Conclusion Hesperetin induces Notch1 expression in carcinoid cells, subsequently suppressing tumor cell proliferation and bioactive hormone production. This provides evidence for further study into hesperetin as a potential treatment for carcinoid cancer.

  • Notch in the development of thyroid C-cells and the treatment of medullary thyroid cancer.
    American journal of translational research, 2010
    Co-Authors: Mackenzie R. Cook, Herbert Chen
    Abstract:

    The Notch pathway plays an important role in the normal development of neuroendocrine cells, including the calcitonin producing C-cells of the thyroid. This effect has been elucidated to be mediated through modulation of AchaeteScute Complex Like 1 (ASCL1), a transcription factor associated with poor prognosis in neuroendocrine cancer. Medullary thyroid cancer (MTC) is one of the neuroendocrine cancers derived from the thyroid C-cells. The Notch pathway has been shown to be inactive in MTC which may lead to altered expression of ASCL1. Artificial induction of Notch signaling in MTC cells can suppress ASCL1 expression, the cell growth as well as hormone secreting potential. Pharmacological activation of the Notch pathway also successfully suppresses the tumor growth in an animal model, which sheds light on the targeted therapy of Notch as a potential treatment for intractable MTC.

Pat Simpson – One of the best experts on this subject based on the ideXlab platform.

  • The AchaeteScute Complex in Diptera: patterns of noncoding sequence evolution
    Journal of evolutionary biology, 2015
    Co-Authors: Bárbara Negre, Pat Simpson
    Abstract:

    The AchaeteScute Complex (AS-C) has been a useful paradigm for the study of pattern formation and its evolution. AchaeteScute genes have duplicated and evolved distinct expression patterns during the evolution of cyclorraphous Diptera. Are the expression patterns in different species driven by conserved regulatory elements? If so, when did such regulatory elements arise? Here, we have sequenced most of the AS-C of the fly Calliphora vicina (including the genes Achaete, Scute and lethal of Scute) to compare noncoding sequences with known cis-regulatory sequences in Drosophila. The organization of the Complex is conserved with respect to Drosophila species. There are numerous small stretches of conserved noncoding sequence that, in spite of high sequence turnover, display binding sites for known transcription factors. Synteny of the blocks of conserved noncoding sequences is maintained suggesting not only conservation of the position of regulatory elements but also an origin prior to the divergence between these two species. We propose that some of these enhancers originated by duplication with their target genes.

  • the Achaete Scute Complex in diptera patterns of noncoding sequence evolution
    Journal of Evolutionary Biology, 2015
    Co-Authors: Bárbara Negre, Pat Simpson
    Abstract:

    The AchaeteScute Complex (AS-C) has been a useful paradigm for the study of pattern formation and its evolution. AchaeteScute genes have duplicated and evolved distinct expression patterns during the evolution of cyclorraphous Diptera. Are the expression patterns in different species driven by conserved regulatory elements? If so, when did such regulatory elements arise? Here, we have sequenced most of the AS-C of the fly Calliphora vicina (including the genes Achaete, Scute and lethal of Scute) to compare noncoding sequences with known cis-regulatory sequences in Drosophila. The organization of the Complex is conserved with respect to Drosophila species. There are numerous small stretches of conserved noncoding sequence that, in spite of high sequence turnover, display binding sites for known transcription factors. Synteny of the blocks of conserved noncoding sequences is maintained suggesting not only conservation of the position of regulatory elements but also an origin prior to the divergence between these two species. We propose that some of these enhancers originated by duplication with their target genes.

  • Evolution of the AchaeteScute Complex in insects: convergent duplication of proneural genes.
    Trends in genetics : TIG, 2009
    Co-Authors: Bárbara Negre, Pat Simpson
    Abstract:

    Proneural genes encode transcriptional activators of the basic Helix–loop–helix class that are involved in neuronal specification and differentiation. We have used the recent availability of genome sequences of multiple distant insect species to study the evolution of a family of proneural genes, the AchaeteScute genes, and to examine their genomic organization and evolution. We document independent evolution of multiple copies of AchaeteScute homologues and argue that this might have contributed to morphological diversity in Diptera and Lepidoptera.

Douglas W Ball – One of the best experts on this subject based on the ideXlab platform.

  • AchaeteScute Complex Homologue 1 Regulates Tumor-Initiating Capacity in Human Small Cell Lung Cancer
    Cancer research, 2009
    Co-Authors: Tianyun Jiang, Brendan J Collins, Barry D. Nelkin, Ning Jin, David N. Watkins, Malcolm V. Brock, William Matsui, Douglas W Ball
    Abstract:

    The basic helix-loop-helix transcription factor AchaeteScute Complex homologue 1 (ASCL1) is essential for the development of normal lung neuroendocrine cells as well as other endocrine and neural tissues. Small cell lung cancer (SCLC) and non-SCLC with neuroendocrine features express ASCL1, where the factor may play a role in the virulence and primitive neuroendocrine phenotype of these tumors. In this study, RNA interference knockdown of ASCL1 in cultured SCLC resulted in inhibition of soft agar clonogenic capacity and induction of apoptosis. cDNA microarray analyses bolstered by expression studies, flow cytometry, and chromatin immunoprecipitation identified two candidate stem cell marker genes, CD133 and aldehyde dehydrogenase 1A1 (ALDH1A1), to be directly regulated by ASCL1 in SCLC. In SCLC direct xenograft tumors, we detected a relatively abundant CD133(high)-ASCL1(high)-ALDH1(high) subpopulation with markedly enhanced tumorigenicity compared with cells with weak CD133 expression. Tumorigenicity in the CD133(high) subpopulation depended on continued ASCL1 expression. Whereas CD133(high) cells readily reconstituted the range of CD133 expression seen in the original xenograft tumor, CD133(low) cells could not. Our findings suggest that a broad range of SCLC cells has tumorigenic capacity rather than a small discrete population. Intrinsic tumor cell heterogeneity, including variation in key regulatory factors such as ASCL1, can modulate tumorigenicity in SCLC.

  • regulation of neuroendocrine differentiation in gastrointestinal carcinoid tumor cells by notch signaling
    The Journal of Clinical Endocrinology and Metabolism, 2005
    Co-Authors: Eric K Nakakura, Virote Sriuranpong, Muthusamy Kunnimalaiyaan, Edward C. Hsiao, Kornel E Schuebel, Michael Borges, Brendan J Collins, Barry D. Nelkin, Herbert Chen, Douglas W Ball
    Abstract:

    Context: Gastrointestinal (GI) carcinoid tumors elaborate serotonin and other vasoactive substances, causing the carcinoid syndrome. Based on developmental biology data, we hypothesized that basic helix-loop-helix transcription factors, including AchaeteScute Complex homolog-like 1 (Ascl1)/hASH1, and the Notch signaling pathway might regulate the neuroendocrine phenotype in GI carcinoids. Objective: The aim of this study was to evaluate expression of developmental transcription factors and Notch signaling components in GI carcinoids and model their interaction in a relevant GI carcinoid cell line. Design: Fourteen GI carcinoid tumor specimens, five paired adjacent normal tissues, fetal tissues, and tumor cell lines were analyzed by RT-PCR and immunoblot. BON carcinoid cells were further analyzed after Notch overexpression for neuroendocrine marker expression, serotonin production, and growth. Setting: The study was conducted in an academic referral center. Patients or Other Participants: Deidentified arc…