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Articles 1 - 9 of 9
Full-Text Articles in Life Sciences
Systematic Screen Of Chemotherapeutics In Drosophila Stem Cell Tumors, Michele Markstein, Samantha Detorree, Julio Cho, Ralph Neumüller, Soren Craig-Müller, Norbert Perrimon
Systematic Screen Of Chemotherapeutics In Drosophila Stem Cell Tumors, Michele Markstein, Samantha Detorree, Julio Cho, Ralph Neumüller, Soren Craig-Müller, Norbert Perrimon
Michele Markstein
Here we report the development of an in vivo system to study the interaction of stem cells with drugs using a tumor model in the adult Drosophila intestine. Strikingly, we find that some Food and Drug Administration-approved chemotherapeutics that can inhibit the growth of Drosophila tumor stem cells can paradoxically promote the hyperproliferation of their wild-type counterparts. These results reveal an unanticipated side effect on stem cells that may contribute to tumor recurrence. We propose that the same side effect may occur in humans based on our finding that it is driven in Drosophila by the evolutionarily conserved Janus kinase-signal …
Gene Expression Profiling Identifies The Zinc-Finger Protein Charlatan As A Regulator Of Intestinal Stem Cells In Drosophila, Alla Amcheslavsky, Yingchao Nie, Qi Li, Feng He, Michele Markstein, Yt Ip, Leo Tsuda
Gene Expression Profiling Identifies The Zinc-Finger Protein Charlatan As A Regulator Of Intestinal Stem Cells In Drosophila, Alla Amcheslavsky, Yingchao Nie, Qi Li, Feng He, Michele Markstein, Yt Ip, Leo Tsuda
Michele Markstein
Intestinal stem cells (ISCs) in the adult Drosophila midgut can respond to tissue damage and support repair. We used genetic manipulation to increase the number of ISC-like cells in the adult midgut and performed gene expression profiling to identify potential ISC regulators. A detailed analysis of one of these potential regulators, the zinc-finger protein Charlatan, was carried out. MARCM clonal analysis and RNAi in precursor cells showed that loss of Chn function caused severe ISC division defects, including loss of EdU incorporation, phosphorylated histone 3 staining and expression of the mitotic protein Cdc2. Loss of Charlatan also led to a …
Modeling Colorectal Cancer As A 3-Dimensional Disease In A Dish: The Case For Drug Screening Using Organoids, Zebrafish, And Fruit Flies, Michele Markstein
Modeling Colorectal Cancer As A 3-Dimensional Disease In A Dish: The Case For Drug Screening Using Organoids, Zebrafish, And Fruit Flies, Michele Markstein
Michele Markstein
This review discusses recent shifts in the understanding of colorectal cancer as a stem cell based disease, based on findings that tie patient prognosis to the presence of cancer stem cells in colorectal tumors. Currently no drugs specifically target CSCs in colorectal tumors. However, recent advances in the culturing of colorectal stem cells using mammalian organoids, zebrafish, and Drosophila offer promising avenues for anti-CSC drug discovery.
Complementary Genomic Screens Identify Serca As A Therapeutic Target In Notch1 Mutated Cancer, G. Roti, A. Carlton, Kn. Ross, Michele Markstein, K. Pajcini, A. H. Su, N. Perrimon, W. S. Pear, A. L. Kung, S. C. Blacklow, J. C. Aster, K. Stegmaier
Complementary Genomic Screens Identify Serca As A Therapeutic Target In Notch1 Mutated Cancer, G. Roti, A. Carlton, Kn. Ross, Michele Markstein, K. Pajcini, A. H. Su, N. Perrimon, W. S. Pear, A. L. Kung, S. C. Blacklow, J. C. Aster, K. Stegmaier
Michele Markstein
Notch1 is a rational therapeutic target in several human cancers, but as a transcriptional regulator, it poses a drug discovery challenge. To identify Notch1 modulators, we performed two cell-based, high-throughput screens for small-molecule inhibitors and cDNA enhancers of a NOTCH1 allele bearing a leukemia-associated mutation. Sarco/endoplasmic reticulum calcium ATPase (SERCA) channels emerged at the intersection of these complementary screens. SERCA inhibition preferentially impairs the maturation and activity of mutated Notch1 receptors and induces a G0/G1 arrest in NOTCH1-mutated human leukemia cells. A small-molecule SERCA inhibitor has on-target activity in two mouse models of human leukemia and interferes with Notch signaling …
Transient Pharmacologic Lowering Of Aβ Production Prior To Deposition Results In Sustained Reduction Of Amyloid Plaque Pathology, Pritam Das, Christophe Verbeeck, Lisa Minter, Paramita Chakrabarty, Kevin Felsenstein, Thomas Kukar, Ghulam Maharvi, Abdul Fauq, Barbara A. Osborne, Todd E. Golde
Transient Pharmacologic Lowering Of Aβ Production Prior To Deposition Results In Sustained Reduction Of Amyloid Plaque Pathology, Pritam Das, Christophe Verbeeck, Lisa Minter, Paramita Chakrabarty, Kevin Felsenstein, Thomas Kukar, Ghulam Maharvi, Abdul Fauq, Barbara A. Osborne, Todd E. Golde
Barbara A. Osborne
Background: Alzheimer’s disease (AD) is the leading cause of dementia among the elderly. Disease modifying therapies targeting Aβ that are in development have been proposed to be more effective if treatment was initiated prior to significant accumulation of Aβ in the brain, but optimal timing of treatment initiation has not been clearly established in the clinic. We compared the efficacy of transient pharmacologic reduction of brain Aβ with a γ-secretase inhibitor (GSI ) for 1–3 months (M) treatment windows in APP Tg2576 mice and subsequent aging of the mice to either 15M or 18M. Results: These data show that reducing …
Exploiting Position Effects And The Gypsy Retrovirus Insulator To Engineer Precisely Expressed Transgenes, Michele Markstein, Chrysoula Pitsouli, Christians Villalta, Susan E. Celniker, Norbert Perrimon
Exploiting Position Effects And The Gypsy Retrovirus Insulator To Engineer Precisely Expressed Transgenes, Michele Markstein, Chrysoula Pitsouli, Christians Villalta, Susan E. Celniker, Norbert Perrimon
Michele Markstein
A major obstacle to creating precisely expressed transgenes lies in the epigenetic effects of the host chromatin that surrounds them. Here we present a strategy to overcome this problem, employing a Gal4-inducible luciferase assay to systematically quantify position effects of host chromatin and the ability of insulators to counteract these effects at phiC31 integration loci randomly distributed throughout the Drosophila genome. We identify loci that can be exploited to deliver precise doses of transgene expression to specific tissues. Moreover, we uncover a previously unrecognized property of the gypsy retrovirus insulator to boost gene expression to levels severalfold greater than at …
Immunity Regulatory Dnas Share Common Organizational Features In Drosophila, Kate Senger, Grant W. Armstrong, William J. Rowell, Jennifer M. Kwan, Michele Markstein, Michael Levine
Immunity Regulatory Dnas Share Common Organizational Features In Drosophila, Kate Senger, Grant W. Armstrong, William J. Rowell, Jennifer M. Kwan, Michele Markstein, Michael Levine
Michele Markstein
Infection results in the rapid activation of immunity genes in the Drosophila fat body. Two classes of transcription factors have been implicated in this process: the REL-containing proteins, Dorsal, Dif, and Relish, and the GATA factor Serpent. Here we present evidence that REL-GATA synergy plays a pervasive role in the immune response. SELEX assays identified consensus binding sites that permitted the characterization of several immunity regulatory DNAs. The distribution of REL and GATA sites within these DNAs suggests that most or all fat-specific immunity genes contain a common organization of regulatory elements: closely linked REL and GATA binding sites positioned …
Decoding Cis-Regulatory Dnas In The Drosophila Genome, Michele Markstein, Michael Levine
Decoding Cis-Regulatory Dnas In The Drosophila Genome, Michele Markstein, Michael Levine
Michele Markstein
Cis-regulatory DNAs control the timing and sites of gene expression during metazoan development. Changes in gene expression are responsible for the morphological diversification of metazoan body plans. However, traditional methods for the identification and characterization of cis-regulatory DNAs are tedious. During the past year, computational methods have been used to identify novel cis-DNAs within the entire Drosophila genome. These methods change the way that cis-DNAs will be analyzed in future studies and offer the promise of unraveling complex gene networks.
Genome-Wide Analysis Of Clustered Dorsal Binding Sites Identifies Putative Target Genes In The Drosophila Embryo, Michele Markstein, Peter Markstein, Vicky Markstein, Michael Levine
Genome-Wide Analysis Of Clustered Dorsal Binding Sites Identifies Putative Target Genes In The Drosophila Embryo, Michele Markstein, Peter Markstein, Vicky Markstein, Michael Levine
Michele Markstein
Metazoan genomes contain vast tracts of cis-regulatory DNA that have been identified typically through tedious functional assays. As a result, it has not been possible to uncover a cis-regulatory code that links primary DNA sequences to gene expression patterns. In an initial effort to determine whether coordinately regulated genes share a common “grammar,” we have examined the distribution of Dorsal recognition sequences in the Drosophila genome. Dorsal is one of the best-characterized sequence-specific transcription factors in Drosophila. The homeobox gene zerknullt (zen) is repressed directly by Dorsal, and this repression is mediated by a 600-bp silencer, the ventral repression element …