Multiple Signaling Pathways Converge on the Cbfa1/Runx2 Transcription Factor to Regulate Osteoblast Differentiation

AbstractMany diseases, including cancer, stem from aberrant activation and overexpression of oncoproteins that are associated with multiple signaling pathways. Although proteins with catalytic activity are able to be successfully drugged, the majority of other protein families, such as transcription factors, remain intractable due to their lack of ligandable sites. In this study, we report the development of TRAnscription Factor TArgeting Chimeras (TRAFTACs) as a generalizable strategy for targeted transcription-factor degradation. Herein, we show that TRAFTACs, which consist of a chimeric oligonucleotide that simultaneously binds to the transcription-factor of interest (TOI) and to HaloTag fused dCas9 protein, can induce degradation of the former via the proteasomal pathway. Application of TRAFTACs to two oncogenic TOIs, NF-κB and brachyury, suggests that TRAFTACs can be successfully employed for the targeted degradation of other DNA-binding proteins with minor changes to the chimeric oligonucleotide.

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APP-007 Multiple signaling pathways contributed to the up-regulation of the novel co-transcription factor mZHX1 by IL-2

The Japanese Journal of Urology ◽

10.5980/jpnjurol.95.316_3 ◽

2004 ◽

Vol 95 (2) ◽

pp. 316

Keyword(s):

Transcription Factor ◽

Signaling Pathways ◽

The Novel ◽

Multiple Signaling

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Faculty Opinions recommendation of UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1004977.58313 ◽

2002 ◽

Author(s):

Eric Long

Keyword(s):

Nk Cells ◽

Signaling Pathways ◽

Mhc Class I ◽

Binding Proteins ◽

Class I ◽

Related Proteins ◽

Multiple Signaling

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Faculty Opinions recommendation of Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1101071.557050 ◽

2008 ◽

Author(s):

E Charles Snow

Keyword(s):

Cell Growth ◽

B Cell ◽

Signaling Pathways ◽

B Lymphocyte ◽

Growth And Survival ◽

B Lymphocyte Stimulator ◽

Multiple Signaling ◽

Cell Growth And Survival

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Faculty Opinions recommendation of Multiple signaling pathways contribute to synergistic TLR ligand-dependent cytokine gene expression in human monocyte-derived macrophages and dendritic cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1156938.617001 ◽

2009 ◽

Author(s):

Stephen Schwartz

Keyword(s):

Gene Expression ◽

Dendritic Cells ◽

Signaling Pathways ◽

Human Monocyte ◽

Cytokine Gene Expression ◽

Cytokine Gene ◽

Multiple Signaling

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Comprehensive assessment of PD-L1 and PD-L2 dysregulation in gastrointestinal cancers

Epigenomics ◽

10.2217/epi-2020-0093 ◽

2020 ◽

Author(s):

Qijie Zhao ◽

Jinan Guo ◽

Yueshui Zhao ◽

Jing Shen ◽

Parham Jabbarzadeh Kaboli ◽

...

Keyword(s):

Transcription Factor ◽

Signaling Pathways ◽

Underlying Mechanism ◽

Comprehensive Analysis ◽

The Cancer Genome Atlas ◽

Gastrointestinal Cancers ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Cancer Genome Atlas ◽

Genome Atlas

Background: PD-L1 and PD-L2 are ligands of PD-1. Their overexpression has been reported in different cancers. However, the underlying mechanism of PD-L1 and PD-L2 dysregulation and their related signaling pathways are still unclear in gastrointestinal cancers. Materials & methods: The expression of PD-L1 and PD-L2 were studied in The Cancer Genome Atlas and Genotype-Tissue Expression databases. The gene and protein alteration of PD-L1 and PD-L2 were analyzed in cBioportal. The direct transcription factor regulating PD-L1/ PD-L2 was determined with ChIP-seq data. The association of PD-L1/PD-L2 expression with clinicopathological parameters, survival, immune infiltration and tumor mutation burden were investigated with data from The Cancer Genome Atlas. Potential targets and pathways of PD-L1 and PD-L2 were determined by protein enrichment, WebGestalt and gene ontology. Results: Comprehensive analysis revealed that PD-L1 and PD-L2 were significantly upregulated in most types of gastrointestinal cancers and their expressions were positively correlated. SP1 was a key transcription factor regulating the expression of PD-L1. Conclusion: Higher PD-L1 or PD-L2 expression was significantly associated with poor overall survival, higher tumor mutation burden and more immune and stromal cell populations. Finally, HIF-1, ERBB and mTOR signaling pathways were most significantly affected by PD-L1 and PD-L2 dysregulation. Altogether, this study provided comprehensive analysis of the dysregulation of PD-L1 and PD-L2, its underlying mechanism and downstream pathways, which add to the knowledge of manipulating PD-L1/PD-L2 for cancer immunotherapy.

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