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SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION: INSIGHTS INTO THE MOLECULAR BASIS OF ORAL CANCER

¹ Department of Biomedical Sciences and ² Department of Diagnostic Sciences and Pathology, University of Maryland, Dental School, 666 West Baltimore Street, Room 4-C-02, Baltimore, MD 21201; and ³ Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201;

View larger version (27K): [in a new window]   Figure 1. Functional domains of STAT proteins. (A) Schematic diagram of a normal STAT molecule and (B) STAT variant harboring a truncation in the C-terminal transactivation domain. N-terminal (NH2), Coiled Coil interactive domain (Coiled Coil), DNA-binding domain (DNABD), Linker domain (Linker), Src-Homology 2 domain (SH2), transactivation domain (TAD), phosphotyrosine (pY) and phosphoserine (pS) residues, and C-terminal (COOH) are depicted.

View larger version (37K): [in a new window]   Figure 2. Model of persistent Stat3 activation and possible modes of regulation in oral squamous carcinoma cells. Mechanisms involving aberrant Stat3 activation may include overexpression of receptors, kinases, and ligands, and de-regulation of positive or negative regulators. Overexpression and overactivation of EGFR and its ligand (TGF-) result in aberrant activation of Stat3, possibly involving constitutive activity of Src kinases. Production of IL-6 and overactivation of gp130 and associated JAK kinases can lead to persistent Stat3 activity. Constitutive Stat3 signaling leads to activation of downstream genes, including anti-apoptotic protein Bcl-XL and cell cycle regulator Cyclin D1. Possible negative regulators of activated Stat3 are also depicted, including Stat3 inducible suppressors of cytokine signaling (SOCS) and protein inhibitors of activated Stat3 (PIAS3). Activation of MAPKs (ERK, JNK, and p38) by MAPK kinases (MEK1/2, MEK4/7, MEK3/6) may also regulate constitutive Stat3 activity through cross-interactions.