Notch: A multi-functional integrating system of microenvironmental signals

LaFoya, Bryce; Munroe, Jordan A.; Mia, Masum M.; Detweiler, Michael Allen; Crow, Jacob J.; Wood, Travis; Roth, Steven; Sharma, Bikram; Albig, Allan R.

doi:10.1016/j.ydbio.2016.08.023

Cited by 83 publications

(62 citation statements)

References 196 publications

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“…The NOTCH signaling pathway is critical in controlling cell-fate decisions during development (19,40). The ligands driven NOTCH signaling is activated when the NOTCH receptors of a signal-sending cell physically interacts with a signal-receiving cell through receptor-ligand interaction.…”

Section: Discussionmentioning

confidence: 99%

“…The NOTCH signaling pathway controls cell-fate decisions during development including differentiation, proliferation, stem cell maintenance and self-renewal of various cell types (19). The NOTCH signaling pathway has complex functions ranging from being tumor suppressor or as an oncogene in a specific cellular context as well as in a signal strength dependent manner (20).…”

Section: Introductionmentioning

confidence: 99%

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Synergistic Activity with NOTCH Inhibition and Androgen Ablation in ERG-Positive Prostate Cancer Cells

Mohamed

Tan

Xavier

et al. 2017

Molecular Cancer Research

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The oncogenic activation of the ETS related gene (ERG) due to gene fusions is present in over half of prostate cancer (CaP) in Western countries. Due to its high incidence and oncogenic role, ERG and components of ERG network have emerged as potential drug targets for CaP. Utilizing gene expression datasets, from matched normal and prostate tumor epithelial cells, an association of NOTCH transcription factors with ERG expression status was identified; confirming that NOTCH factors are direct transcriptional targets of ERG. Inhibition of ERG in TMPRSS2-ERG positive VCaP cells led to decreased levels of NOTCH-1 and -2 proteins and downstream transcriptional targets and partially recapitulated the phenotypes associated with ERG inhibition. Regulation of NOTCH-1 and -2 genes by ERG were also noted with ectopic ERG expression in LNCaP (ERG-negative CaP) and RWPE-1 (benign prostate derived immortalized) cells. Furthermore, inhibition of NOTCH by the small molecule gamma-Secretase inhibitor 1, GSI-1, conferred an increased sensitivity to androgen receptor (AR) inhibitors (Bicalutamide, Enzalutamide,) or the androgen biosynthesis inhibitor (Abiraterone) in VCaP cells. Combined treatment with Bicalutamide and GSI-1 showed strongest inhibition of AR, ERG, NOTCH1, NOTCH2, and PSA protein levels along with decreased cell growth, cell survival and enhanced apoptosis. Intriguingly, this effect was not observed in ERG-negative prostate cancer cells or immortalized benign/normal prostate epithelial cells. These data underscore the synergy of AR and NOTCH inhibitors in reducing the growth of ERG-positive CaP cells. Implications Combinational targeting of NOTCH and AR signaling has therapeutic potential in advanced ERG-driven prostate cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synergistic Activity with NOTCH Inhibition and Androgen Ablation in ERG-Positive Prostate Cancer Cells

Mohamed

Tan

Xavier

et al. 2017

Molecular Cancer Research

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“…The Notch system consists of five ligands that signal promiscuously through four receptors to activate target gene transcription (21). The receptors Notch 1 and Notch 2 are expressed at every stage of the T cell lifecycle, and Notch signaling has demonstrated importance in thymic maturation (22, 23), effector function (24, 25), and the formation and maintenance of immunological memory (26).…”

Section: Introductionmentioning

confidence: 99%

Systemic Expression of Notch Ligand Delta-Like 4 during Mycobacterial Infection Alters the T Cell Immune Response

et al. 2016

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The Notch ligand delta-like 4 (DLL4) is known to fine-tune the CD4+ T cell cytokine response. DLL4 is expressed on the surface of antigen-presenting cells (APCs) in a MyD88-dependent manner. We found that DLL4 expression was upregulated on bone marrow progenitor cells and APCs in mice infected with BCG Mycobacterium. Transfer of DLL4+ progenitor cells from infected hosts resulted in an increase DLL4+ myeloid cells in the spleen, indicating that expression of the dll4 gene is propagated throughout hematopoiesis. We also found an increase in DLL4+ monocytes from individuals who were infected with Mycobacterium tuberculosis. In latent individuals, DLL4 expression correlated with increased cytokine production from T cells in response to PPD stimulation. Finally, antibody blockade of DLL4 reduced T cell cytokine production from naïve T cells stimulated with antigen. These results demonstrate that the Notch ligand DLL4 can influence T cell cytokine production in both humans and mice, and further reveal that expression of DLL4 is upregulated on early hematopoietic progenitors in response to chronic mycobacterial infection. These data suggest that widespread DLL4 expression may occur as a result of mycobacterial infection, and that this expression may alter CD4+ T cell responses to both previously encountered and novel antigens.

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“…These mechanical forces pull cells apart leading to proteolytic activation of Notch while tight junctions holding cells together apparently counteract against the pull [14, 48, 49]. This process contributes to Notch signaling pathway’s ability to integrate multiple micro-environmental signals and sense cell-cell interaction, trigging the downstream Notch signaling target HES1 transcription [50, 51]. Thus, cell shapes can affect the Notch signaling triggered events [52].…”

Section: Data Notesmentioning

confidence: 99%

Rotational 3D mechanogenomic Turing patterns of human colon Caco-2 cells during differentiation

Zheng

Kalinin

Dinov

et al. 2018

Preprint

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Recent reports suggest that actomyosin meshwork act in a mechanobiological manner alter cell/nucleus/tissue morphology, including human colon epithelial Caco-2 cancer cells that form polarized 2D epithelium or 3D sphere/tube when placed in different culture conditions. We observed the rotational motion of the nucleus in Caco-2 cells in vitro that appears to be driven by actomyosin network prior to the formation of a differentiated confluent epithelium. Caco-2 cell monolayer preparations demonstrated 2D patterns consistent with Allan Turing’s “gene morphogen” hypothesis based on live cell imaging analysis of apical tight junctions indicating the actomyosin meshwork. Caco-2 cells in 3D culture are frequently used as a model to study 3D epithelial morphogenesis involving symmetric and asymmetric cell divisions. Differentiation of Caco-2 cells in vitro demonstrated similarity to intestinal enterocyte differentiation along the human colon crypt axis. We observed rotational 3D patterns consistent with gene morphogens during Caco-2 cell differentiation. Single- to multi-cell ring/torus-shaped genomes were observed that were similar to complex fractal Turing patterns extending from a rotating torus centre in a spiral pattern consistent with gene morphogen motif. Rotational features of the epithelial cells may contribute to well-described differentiation from stem cells to the luminal colon epithelium along the crypt axis. This dataset may be useful to study the role of mechanobiological processes and the underlying molecular mechanisms as determinants of cellular and tissue architecture in space and time, which is the focal point of the 4D nucleome initiative.

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Notch: A multi-functional integrating system of microenvironmental signals

Cited by 83 publications

References 196 publications

Synergistic Activity with NOTCH Inhibition and Androgen Ablation in ERG-Positive Prostate Cancer Cells

Synergistic Activity with NOTCH Inhibition and Androgen Ablation in ERG-Positive Prostate Cancer Cells

Systemic Expression of Notch Ligand Delta-Like 4 during Mycobacterial Infection Alters the T Cell Immune Response

Rotational 3D mechanogenomic Turing patterns of human colon Caco-2 cells during differentiation

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