JOURNAL OF CELLULAR PHYSIOLOGY 197:157–168 (2003) REVIEW ARTICLES STAT Proteins: From Normal Control of Cellular Events to Tumorigenesis VALENTINA CALO ` , 1 MANUELA MIGLIAVACCA, 3 VIVIANA BAZAN, 1 MARCELLA MACALUSO, 1,4 MARIA BUSCEMI, 3 NICOLA GEBBIA, 2 AND ANTONIO RUSSO 1 * 1 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 2 Section of Medical Oncology, Department of Oncology, Regional Reference Center for the Biomolecular Characterization of Neoplasms and Genetic Screening of Hereditary Tumors, University of Palermo, Palermo, Italy 3 Section of Histology, Department of Experimental Medicine; University of Palermo, Palermo, Italy 4 Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia 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 angio- genesis 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 IFNg 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, re- sponse 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. J. Cell. Physiol. 197: 157 – 168, 2003. ß 2003 Wiley-Liss, Inc. Signal transducers and activators of transcription (STAT) proteins comprise a family of transcription fac- tors latent in the cytoplasm that consists of seven differ- ent members: STAT1, 2, 3, 4, 5A, 5B, and 6 (Darnell, 1997). These transcription factors are activated by a series of extracellular signaling proteins such as cytokine, growth factors, and hormones that bind to specific cell-surface receptors. The resulting signal transduc- tion pathways permit them to play different roles in normal physiological cell processes, such as differ- entiation, proliferation, apoptosis, and angiogenesis (Horvath, 2000). However, aberrant activation of STAT-signaling gives rise to different pathological events, for example, cell transformation and oncogenesis. Although they neither directly regulate cell-cycle checkpoints nor contribute to the repair of DNA damage, they take part in tumorigen- esis by means of the deregulation of the signal pathways in which they are implicated (Bowman et al., 2000). 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 ß 2003 WILEY-LISS, INC. The authorship is shared equally by Valentina Calo ` and Manuela Migliavacca, and their names are listed in alphabetical order. *Correspondence to: Antonio Russo, Via Veneto 5, 90144 Palermo, Italy. E-mail: Lab-oncobiologia@usa.net Received 31 March 2003; Accepted 17 April 2003 DOI: 10.1002/jcp.10364