1: Expert Opin Ther Targets. 2004 Oct;8(5):409-22. STAT proteins as novel targets for cancer drug discovery. Turkson J. Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, SRB 22214, Tampa, FL 33612, USA. turksonj@moffitt.usf.edu Signal transducer and activator of transcription (STAT) proteins are latent cytoplasmic transcription factors that were discovered in the context of cytokine and growth factor signalling. Normal STAT signalling is tightly controlled with finite kinetics, which is in keeping with standard cellular responses. However, persistent STAT activation has also been observed and is frequently associated with malignant transformation. Constitutive activation of STAT proteins, notably of Stat3 and Stat5, is detected in many human tumour cells and cells transformed by oncoproteins that activate tyrosine kinase signalling pathways. It is well-established that constitutively active Stat3 is one of the molecular abnormalities that has a causal role in oncogenesis. Aberrant Stat3 promotes uncontrolled growth and survival through dysregulation of gene expression, including cyclin D1, c-Myc, Bcl-xL, Mcl-1 and survivin genes, and thereby contributes to oncogenesis. Moreover, recent studies reveal that persistently active Stat3 induces tumour angiogenesis by upregulation of vascular endothelial growth factor induction, and modulates immune functions in favour of tumour immune evasion. Overall, studies have validated Stat3 as a novel target for cancer therapy, and hence provided the rationale for developing small-molecule Stat3 inhibitors. This review will discuss current evidence for the critical role of aberrant STAT signalling in malignant transformation, and examine the validity as well as the therapeutic potential of Stat3 as a cancer target. An update on the efforts to develop novel Stat3 inhibitors for therapeutic application will also be provided. Publication Types: Review PMID: 15469392 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 2: J Cell Physiol. 2003 Nov;197(2):157-68. STAT proteins: from normal control of cellular events to tumorigenesis. Calo V, Migliavacca M, Bazan V, Macaluso M, Buscemi M, Gebbia N, Russo A. Section of Molecular Oncology, Department of Oncology, Regional Reference Center for the Biomolecular Characterization of Neoplasms and Genetic Screening of Hereditary Tumors, University of Palermo, Palermo, Italy. Signal transducers and activators of transcription (STAT) proteins comprise a family of transcription factors latent in the cytoplasm that participate in normal cellular events, such as differentiation, proliferation, cell survival, apoptosis, and angiogenesis following cytokine, growth factor, and hormone signaling. STATs are activated by tyrosine phosphorylation, which is normally a transient and tightly regulates process. Nevertheless, several constitutively activated STATs have been observed in a wide number of human cancer cell lines and primary tumors, including blood malignancies and solid neoplasias. STATs can be divided into two groups according to their specific functions. One is made up of STAT2, STAT4, and STAT6, which are activated by a small number of cytokines and play a distinct role in the development of T-cells and in IFNgamma signaling. The other group includes STAT1, STAT3, and STAT5, activated in different tissues by means of a series of ligands and involved in IFN signaling, development of the mammary gland, response to GH, and embriogenesis. This latter group of STATS plays an important role in controlling cell-cycle progression and apoptosis and thus contributes to oncogenesis. Although an increased expression of STAT1 has been observed in many human neoplasias, this molecule can be considered a potential tumor suppressor, since it plays an important role in growth arrest and in promoting apoptosis. On the other hand, STAT3 and 5 are considered as oncogenes, since they bring about the activation of cyclin D1, c-Myc, and bcl-xl expression, and are involved in promoting cell-cycle progression, cellular transformation, and in preventing apoptosis. Publication Types: Review Review, Tutorial PMID: 14502555 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 3: Gastroenterology. 2002 Apr;122(4):1020-34. Interferon-alpha activates multiple STAT signals and down-regulates c-Met in primary human hepatocytes. Radaeva S, Jaruga B, Hong F, Kim WH, Fan S, Cai H, Strom S, Liu Y, El-Assal O, Gao B. Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA. BACKGROUND & AIMS: Interferon (IFN)-alpha therapy is currently the primary choice for viral hepatitis and a promising treatment for hepatocellular carcinoma (HCC). Primary mouse and rat hepatocytes respond poorly to IFN-alpha stimulation. Thus, it is very important to examine the IFN-alpha signal pathway in primary human hepatocytes. METHODS: The IFN-alpha-activated signals and genes in primary human hepatocytes and hepatoma cells were examined by Western blotting and microarray analyses. RESULTS: Primary human hepatocytes respond very well to IFN-alpha stimulation as shown by activation of multiple signal transducer and activator of transcription factor (STAT) 1, 2, 3, 5, and multiple genes. The differential response to IFN-alpha stimulation in primary human and mouse hepatocytes may be caused by expression of predominant functional IFN-alpha receptor 2c (IFNAR2c) in primary human hepatocytes vs. expression of predominant inhibitory IFNAR2a in mouse hepatocytes. Microarray analyses of primary human hepatocytes show that IFN-alpha up-regulates about 44 genes by over 2-fold and down-regulates about 9 genes by 50%. The up-regulated genes include a variety of antiviral and tumor suppressors/proapoptotic genes. The down-regulated genes include c-myc and c-Met, the hepatocyte growth factor (HGF) receptor. Down-regulation of c-Met is caused by IFN-alpha suppression of the c-Met promoter through down-regulation of Sp1 binding and results in attenuation of HGF-induced signals and cell proliferation. CONCLUSIONS: IFN-alpha directly targets human hepatocytes, followed by activation of multiple STATs and regulation of a wide variety of genes, which may contribute to the antiviral and antitumor activities of IFN-alpha in human liver. PMID: 11910354 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 4: Cell. 1999 Jan 8;96(1):121-30. Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNgamma-mediated signaling. Zhu M, John S, Berg M, Leonard WJ. Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1674, USA. Using the coiled-coil region of Stat5b as the bait in a yeast two-hybrid screen, we identified the association of Nmi, a protein of unknown function previously reported as an N-Myc interactor. We further show that Nmi interacts with all STATs except Stat2. We evaluated two cytokine systems, IL-2 and IFNgamma, and demonstrate that Nmi augments STAT-mediated transcription in response to these cytokines. Interestingly, Nmi lacks an intrinsic transcriptional activation domain; instead, Nmi enhances the association of CBP/p300 coactivator proteins with Stat1 and Stat5, and together with CBP/p300 can augment IL-2- and IFNgamma-dependent transcription. Therefore, our data not only reveal that Nmi can potentiate STAT-dependent transcription, but also suggest that it can augment coactivator protein recruitment to at least some members of a group of sequence-specific transcription factors. PMID: 9989503 [PubMed - indexed for MEDLINE] ---------------------------------------------------------------