Dataset Information

Dynarrestin, a novel inhibitor of cytoplasmic dyneins 1 and 2

ABSTRACT: Aberrant hedgehog (Hh) signaling contributes to the pathogenesis of multiple cancers. Currently available inhibitors target Smoothened, which can acquire mutations causing drug resistance. Thus, compounds that inhibit Hh signaling downstream of Smoothened are urgently needed. We identified dynarrestin, a novel inhibitor of cytoplasmic dyneins 1 and 2 by using achemical proteomics approach. Dynarrestin acts reversibly to inhibit cytoplasmic dynein 1-dependent microtubule binding and motility in vitro without affecting ATP hydrolysis. It rapidly and reversibly inhibits endosome movement in living cells and perturbs mitosis by inducing spindle misorientation and a pseudoprometaphase delay. Dynarrestin reversibly inhibits intraflagellar transport (IFT) of the cargo IFT88 and flux of Smoothened within cilia without interfering with ciliogenesis as well as suppresses Hh-dependent proliferation of neuronal precursors and tumor cells. As such, dynarrestin is a valuable new tool for probing cytoplasmic dynein-dependent cellular processes and a promising lead compound for medicinal chemistry programs aimed at development of anti-cancer drugs.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Embryonic Fibroblast

DISEASE(S): Sarcoma

SUBMITTER: Hannes Drexler

LAB HEAD: Hannes C. A. Drexler

PROVIDER: PXD004440 | Pride | 2018-08-08

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	20111202_exp0358_AN_Nancy_LDC-Hedgehoc_Ingel_01.raw	Raw
	20111202_exp0358_AN_Nancy_LDC-Hedgehoc_Ingel_02.raw	Raw
	20111202_exp0358_AN_Nancy_LDC-Hedgehoc_Ingel_03.raw	Raw
	20111202_exp0358_AN_Nancy_LDC-Hedgehoc_Ingel_04.raw	Raw
	20111202_exp0358_AN_Nancy_LDC-Hedgehoc_Ingel_05.raw	Raw

Items per page:

1 - 5 of 140

Publications

Dynarrestin, a Novel Inhibitor of Cytoplasmic Dynein.

Höing Susanne S Yeh Ting-Yu TY Baumann Matthias M Martinez Nancy E NE Habenberger Peter P Kremer Lea L Drexler Hannes C A HCA Küchler Philipp P Reinhardt Peter P Choidas Axel A Zischinsky Mia-Lisa ML Zischinsky Gunther G Nandini Swaran S Ledray Aaron P AP Ketcham Stephanie A SA Reinhardt Lydia L Abo-Rady Masin M Glatza Michael M King Stephen J SJ Nussbaumer Peter P Ziegler Slava S Klebl Bert B Schroer Trina A TA Schöler Hans R HR Waldmann Herbert H Sterneckert Jared J

Cell chemical biology 20180127 4

Aberrant hedgehog (Hh) signaling contributes to the pathogenesis of multiple cancers. Available inhibitors target Smoothened (Smo), which can acquire mutations causing drug resistance. Thus, compounds that inhibit Hh signaling downstream of Smo are urgently needed. We identified dynarrestin, a novel inhibitor of cytoplasmic dyneins 1 and 2. Dynarrestin acts reversibly to inhibit cytoplasmic dynein 1-dependent microtubule binding and motility in vitro without affecting ATP hydrolysis. It rapidly ...[more]

PMID: 29396292

Similar Datasets

Project description:The need for an efficient carcinogenicity test prompted this study, in which we used a microarray-based genomics approach, with a short-term in vivo model, in combination with insights from statistical and mechanistic analyses. We performed additional experiments to support the significance of the microarray results. Carcinogens were evaluated based on differences in the mechanisms involved in the response to genotoxic (GTX) carcinogens and non-genotoxic (NGTX) carcinogens. Microarray data were analyzed for 2 time points after treatment with the following 6 carcinogens. The analysis was performed using t-tests to compare the fold changes, and we selected differentially expressed genes (DEGs) and evaluated the reasons for differential expression in terms of cellular pathways and processes. We mapped the DEG-related pathways to analyze cellular processes, and we were able to uncover significant mechanisms that involve critical cellular components, such as CDKN1A (p21) and BAX. In addition, a comparison of the data from two time points showed that the repeated administration model was more effective than a single administration for carcinogen research. The classification analysis of selected DEGs was performed by setting microarray data of 4 carcinogens as test sets; these test sets were evaluated as classifiers. Microarray results were further supported using the Comet and micronucleus assays. It was found that gene expression profiling using microarrays, followed by pathway analysis, was effective in increasing the understanding of the characteristics of different carcinogens, and the efficiency of these methods was exemplified by the short-term (3 day) nature of the animal experiments. The following 10 hepatocarcinogens were used: 2-acetylaminofluorene (53-96-3), diethylnitrosamine (55-18-5), 4-dimethylamino-3'-methyl azobenzene (55-80-1), clofibrate (637-07-0), 1,4-dioxane (123-91-1), DL-ethionine (67-21-0), 1,3-dichloro-2'-propanol (96-23-1), urethane (51-79-6), sodium nitrite (7632-00-0), and methyleugenol (93-15-2). Forty-one data were obtained for the training compounds in this study. We treated rats with one of three compounds or a control for each GTX and NGTX experimental group and measured 2 time points for each group. All experimental procedures were repeated three times. We excluded 1 file that was found to be a failure. Each ‘.CEL’ file obtained as a raw data file was standardized using the RMA (Robust Multi-array Average) algorithm.