Abstract
Members of the signal transducers and activators of transcription (STAT) pathway, which were originally identified as key components linking cytokine signals to transcriptional events in cells, have recently been demonstrated to have a major role in cancer. They are cytoplasmic proteins that form functional dimers with each other when activated by tyrosine phosphorylation. Activated STAT proteins translocate to the nucleus to regulate expression of genes by binding to specific elements within gene promoters. Constitutive activation of the STAT family members Stat3 and Stat5, and/or loss of Stat1 signaling, is found in a large group of diverse tumors. Increasing evidence demonstrates that STAT proteins can regulate many pathways important in oncogenesis including cell-cycle progression, apoptosis, tumor angiogenesis, tumor-cell invasion and metastasis, and tumor-cell evasion of the immune system. Based on these findings, a growing effort is underway to target STAT proteins directly and indirectly for cancer therapy. This review will highlight STAT signaling pathways, STAT target genes involved in cancer, evidence for STAT activation in human cancers, and therapeutic strategies to target STAT molecules for anticancer therapy.
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Acknowledgements
The authors wish to thank members of their laboratories, colleagues who have contributed to the studies described, and acknowledge the important work of other investigators that could not be cited because of space limitations. Special thanks to Becky Alexander for administrative assistance.
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Glossary
- SRC-HOMOLOGY-2 (SH2)DOMAINS
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Stretches of approximately 100 amino acids often found in signal transduction proteins, which confer binding to phosphorylated tyrosine residues within other signaling proteins
- GENE ASSOCIATED WITH RETINOID-INTERFERONINDUCED MORTALITY 19(GRIM 19)
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The product of a cell-death regulatory gene induced by interferon-beta and retinoic acid
- BYSTANDER EFFECT
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Tumor regression when a fraction of the tumor mass is genetically modified
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Haura, E., Turkson, J. & Jove, R. Mechanisms of Disease: insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Rev Clin Oncol 2, 315–324 (2005). https://doi.org/10.1038/ncponc0195
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DOI: https://doi.org/10.1038/ncponc0195
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