Role of Dynein Light Chain 1 in Tamoxifen Resistance in Breast Cancer

Cytoplasmic dynein is a large multisubunit complex involved in retrograde transport and the positioning of various organelles. Dynein light chain (LC) subunits are conserved across species; however, the molecular contribution of LCs to dynein function remains controversial. One model suggests that LCs act as cargo-binding scaffolds. Alternatively, LCs are proposed to stabilize the intermediate chains (ICs) of the dynein complex. To examine the role of LCs in dynein function, we used Saccharomyces cerevisiae, in which the sole function of dynein is to position the spindle during mitosis. We report that the LC8 homologue, Dyn2, localizes with the dynein complex at microtubule ends and interacts directly with the yeast IC, Pac11. We identify two Dyn2-binding sites in Pac11 that exert differential effects on Dyn2-binding and dynein function. Mutations disrupting Dyn2 elicit a partial loss-of-dynein phenotype and impair the recruitment of the dynein activator complex, dynactin. Together these results indicate that the dynein-based function of Dyn2 is via its interaction with the dynein IC and that this interaction is important for the interaction of dynein and dynactin. In addition, these data provide the first direct evidence that LC occupancy in the dynein motor complex is important for function.

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Dynein Light Chain 1 Regulates Dynamin-mediated F-Actin Assembly during Sperm Individualization in Drosophila

Molecular Biology of the Cell ◽

10.1091/mbc.e05-02-0103 ◽

2005 ◽

Vol 16 (7) ◽

pp. 3107-3116 ◽

Cited By ~ 29

Author(s):

Anindya Ghosh-Roy ◽

Bela S. Desai ◽

Krishanu Ray

Keyword(s):

Light Chain ◽

Cytoplasmic Dynein ◽

Actin Dynamics ◽

Dynein Light Chain ◽

Actin Assembly ◽

Cellular Functions ◽

Directed Movement ◽

Cellular Processes ◽

Dynactin Complex

Toward the end of spermiogenesis, spermatid nuclei are compacted and the clonally related spermatids individualize to become mature and active sperm. Studies in Drosophila showed that caudal end-directed movement of a microfilament-rich structure, called investment cone, expels the cytoplasmic contents of individual spermatids. F-actin dynamics plays an important role in this process. Here we report that the dynein light chain 1 (DLC1) of Drosophila is involved in two separate cellular processes during sperm individualization. It is enriched around spermatid nuclei during postelongation stages and plays an important role in the dynein-dynactin–dependent rostral retention of the nuclei during this period. In addition, DDLC1 colocalizes with dynamin along investment cones and regulates F-actin assembly at this organelle by retaining dynamin along the cones. Interestingly, we found that this process does not require the other subunits of cytoplasmic dynein-dynactin complex. Altogether, these observations suggest that DLC1 could independently regulate multiple cellular functions and established a novel role of this protein in F-actin assembly in Drosophila.

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The Drosophila tctex-1 Light Chain Is Dispensable for Essential Cytoplasmic Dynein Functions but Is Required during Spermatid Differentiation

Molecular Biology of the Cell ◽

10.1091/mbc.e04-01-0013 ◽

2004 ◽

Vol 15 (7) ◽

pp. 3005-3014 ◽

Cited By ~ 41

Author(s):

Min-gang Li ◽

Madeline Serr ◽

Eric A. Newman ◽

Thomas S. Hays

Keyword(s):

Light Chain ◽

Cytoplasmic Dynein ◽

Sperm Nucleus ◽

P Element ◽

Dynein Light Chain ◽

Null Mutant ◽

Multiple Functions ◽

Bona Fide ◽

Adult Organism

Variations in subunit composition and modification have been proposed to regulate the multiple functions of cytoplasmic dynein. Here, we examine the role of the Drosophila ortholog of tctex-1, the 14-kDa dynein light chain. We show that the 14-kDa light chain is a bona fide component of Drosophila cytoplasmic dynein and use P element excision to generate flies that completely lack this dynein subunit. Remarkably, the null mutant is viable and the only observed defect is complete male sterility. During spermatid differentiation, the 14-kDa light chain is required for the localization of a nuclear “cap” of cytoplasmic dynein and for proper attachment between the sperm nucleus and flagellar basal body. Our results provide evidence that the function of the 14-kDa light chain in Drosophila is distinct from other dynein subunits and is not required for any essential functions in early development or in the adult organism.

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Novel linear motif filtering protocol reveals the role of the LC8 dynein light chain in the Hippo pathway

PLoS Computational Biology ◽

10.1371/journal.pcbi.1005885 ◽

2017 ◽

Vol 13 (12) ◽

pp. e1005885 ◽

Cited By ~ 10

Author(s):

Gábor Erdős ◽

Tamás Szaniszló ◽

Mátyás Pajkos ◽

Borbála Hajdu-Soltész ◽

Bence Kiss ◽

...

Keyword(s):

Light Chain ◽

Hippo Pathway ◽

Dynein Light Chain ◽

Linear Motif ◽

The Hippo Pathway

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Interaction of the Rabies Virus P Protein with the LC8 Dynein Light Chain

Journal of Virology ◽

10.1128/jvi.74.21.10212-10216.2000 ◽

2000 ◽

Vol 74 (21) ◽

pp. 10212-10216 ◽

Cited By ~ 214

Author(s):

Hélène Raux ◽

Anne Flamand ◽

Danielle Blondel

Keyword(s):

Rabies Virus ◽

Light Chain ◽

Cytoplasmic Dynein ◽

Dynein Light Chain ◽

Directed Movement ◽

Virus Particles ◽

P Protein ◽

Infected Cells ◽

Transcription And Replication

ABSTRACT The rabies virus P protein is involved in viral transcription and replication but its precise function is not clear. We investigated the role of P (CVS strain) by searching for cellular partners by using a two-hybrid screening of a PC12 cDNA library. We isolated a cDNA encoding a 10-kDa dynein light chain (LC8). LC8 is a component of cytoplasmic dynein involved in the minus end-directed movement of organelles along microtubules. We confirmed that this molecule interacts with P by coimmunoprecipitation in infected cells and in cells transfected with a plasmid encoding P protein. LC8 was also detected in virus particles. Series of deletions from the N- and C-terminal ends of P protein were used to map the LC8-binding domain to the central part of P (residues 138 to 172). These results are relevant to speculate that dynein may be involved in the axonal transport of rabies virus along microtubules through neuron cells.

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Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells

Oncology Reports ◽

10.3892/or.2012.1728 ◽

2012 ◽

Cited By ~ 7

Author(s):

Fukang Xie

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Tamoxifen Resistance ◽

Erk Signaling ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Induced Apoptosis

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miR-489 confines uncontrolled estrogen signaling through a negative feedback mechanism and regulates tamoxifen resistance in breast cancer

10.21203/rs.3.rs-131460/v1 ◽

2020 ◽

Author(s):

Mithil Soni ◽

Ozge Saatci ◽

Yogin Patel ◽

Manikanda Raja Keerthi Raja ◽

Xinfeng Liu ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cell Lines ◽

Tamoxifen Resistance ◽

Resistant Cell ◽

Estrogen Signaling ◽

Breast Cancers ◽

Tamoxifen Resistant ◽

Hormonal Therapies

Abstract Background Approximately 75% of diagnosed breast cancer tumors are Estrogen receptor (ER) positive tumors and are associated with better prognosis due to their response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. In the current study, we aimed to evaluate miR-489 as a novel molecular target to combat tamoxifen resistance.Methods Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen resistant cell lines unveiled the potential role of miR-489 in regulation of estrogen signaling and development of tamoxifen resistance. We manipulated miR-489 expression in breast cancer cell lines by transient transfection of miR-489 mimic or establishment of knockout cell lines using the CRISPR/Cas9 system to study the reciprocal regulation of miR-489 and estrogen/ER signaling pathways. Cell proliferation, tumor sphere formation assay and flow cytometry analysis were conducted to investigate the role of miR-489 on estrogen-induced cell proliferation, cancer stem cells expansion and development of tamoxifen resistance.Results miR-489 expression was significantly downregulated in tamoxifen-resistant cell lines. Low levels of miR-489 were associated with poor clinical outcomes in patients with hormone treatment. In vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen regulated miRNA that negatively regulated estrogen receptor signaling by using at least the following two mechanisms: i) modulation of ER phosphorylation status by inhibiting MAPK and AKT kinase activities; ii) regulation of nucleus to cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 could break the positive feed-forward loop between estrogen-ERα axis and p38 MAPK in breast cancer cells which was necessary for its function as transcription factor.Conclusion Our study unveiled the underlying molecular mechanism by which miR-489 regulates estrogen signaling pathway through a negative feedback loop and uncovered its role in the development of and overcoming tamoxifen resistance in breast cancers.

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