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Signal transducers and activators of transcription 3 (STAT3) directly regulates cytokine-induced fascin expression and is required for breast cancer cell migration.

ABSTRACT: The cytokines oncostatin M (OSM) and IL-6 promote breast cancer cell migration and metastasis. Both cytokines activate STAT3, a member of the STAT (signal transducers and activators of transcription) family of transcription factors. Through transcriptional regulation of its target genes, STAT3 controls a wide range of cellular processes, including cellular proliferation, oncogenesis, and cancer metastasis. Fascin is an actin-bundling protein involved in cell migration. Elevated levels of fascin expression are found in many metastatic cancers, and inhibition of fascin function by small chemical compounds leads to a block of tumor metastasis. In this work, we demonstrate that fascin is a direct STAT3 target gene in response to OSM and IL-6 in both mouse and human breast cancer cells. We show that NF?B also binds to the fascin promoter in response to cytokine treatment and this binding is STAT3-dependent. Both STAT3 and NF?B are required for the cytokine-induced expression of fascin in cancer cells. Furthermore, we demonstrate that STAT3, in directly controlling fascin expression, is both necessary and sufficient for breast cancer cell migration.

SUBMITTER: Snyder M

PROVIDER: S-EPMC3234713 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Signal transducers and activators of transcription 3 (STAT3) directly regulates cytokine-induced fascin expression and is required for breast cancer cell migration.

Snyder Marylynn M Huang Xin-Yun XY Zhang J Jillian JJ

The Journal of biological chemistry 20110920 45

The cytokines oncostatin M (OSM) and IL-6 promote breast cancer cell migration and metastasis. Both cytokines activate STAT3, a member of the STAT (signal transducers and activators of transcription) family of transcription factors. Through transcriptional regulation of its target genes, STAT3 controls a wide range of cellular processes, including cellular proliferation, oncogenesis, and cancer metastasis. Fascin is an actin-bundling protein involved in cell migration. Elevated levels of fascin ...[more]

PMID: 21937440

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Project description:Signal Transducer and Activator of Transcription STAT5 is a key mediator of cell proliferation, differentiation and survival. While STAT5 activity is tightly regulated in normal cells, its constitutive activation directly contributes to oncogenesis and is associated with a broad range of hematological and solid tumor cancers. Therefore the development of compounds able to modulate pathogenic activation of this protein is a very challenging endeavor. A crucial step of drug design is the understanding of the protein conformational features and the definition of putative binding site(s) for such modulators. Currently, there is no structural data available for human STAT5 and our study is the first footprint towards the description of structure and dynamics of this protein. We investigated structural and dynamical features of the two STAT5 isoforms, STAT5a and STAT5b, taken into account their phosphorylation status. The study was based on the exploration of molecular dynamics simulations by different analytical methods. Despite the overall folding similarity of STAT5 proteins, the MD conformations display specific structural and dynamical features for each protein, indicating first, sequence-encoded structural properties and second, phosphorylation-induced effects which contribute to local and long-distance structural rearrangements interpreted as allosteric event. Further examination of the dynamical coupling between distant sites provides evidence for alternative profiles of the communication pathways inside and between the STAT5 domains. These results add a new insight to the understanding of the crucial role of intrinsic molecular dynamics in mediating intramolecular signaling in STAT5. Two pockets, localized in close proximity to the phosphotyrosine-binding site and adjacent to the channel for communication pathways across STAT5, may constitute valid targets to develop inhibitors able to modulate the function-related communication properties of this signaling protein.

Dataset Information

Signal transducers and activators of transcription 3 (STAT3) directly regulates cytokine-induced fascin expression and is required for breast cancer cell migration.

Publications

Signal transducers and activators of transcription 3 (STAT3) directly regulates cytokine-induced fascin expression and is required for breast cancer cell migration.

Similar Datasets

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