Signal transducer and activator of transcription proteins in leukemias

Abstract

IntroductionSignal transducer and activator of transcription (STAT) proteins are a family of latent cytoplasmic transcription factors involved in cytokine, hormone, and growth factor signal transduction. 1-7 STAT proteins mediate broadly diverse biologic processes, including cell growth, differentiation, apoptosis, fetal development, transformation, inflammation, and immune response. The intent of this review is to provide a brief synopsis of the role of STAT activation in signal transduction, the structure of STAT proteins, mechanisms of aberrant signal transduction, and the role of STAT proteins in normal and malignant hematopoiesis. The review focuses in particular on the role of STAT activation in leukemogenesis. STATs in signal transductionThe interaction of a cytokine with its ligand-binding receptor ␣ subunit is the first step in the formation of a signaling-competent receptor complex. This process involves the oligomerization of the ligand-bound subunit with either another subunit or a separate, signal-transducing ␤ subunit. 8,9 This oligomerization initiates the process of signal transduction by activation of the receptorassociated Janus family tyrosine kinases (JAKs) through crossphosphorylation ( Figure 1). Immediate targets of the activated JAKs are the cytoplasmic portions of the receptors and receptorassociated proteins. The tyrosine phosphorylated sites become docking elements for Src homology 2 (SH2)-and phosphotyrosylbinding domain-containing proteins present in the membrane or the cytoplasmic compartment. Prominent among these are the STATs. Receptor-recruited STATs are phosphorylated on a single tyrosine residue in the carboxy terminal portion. The modified STATs are released from the cytoplasmic region of the receptor subunits to form homodimers or heterodimers through reciprocal interaction between the phosphotyrosine of one STAT and the SH2 domain of another. Following dimerization, STATs rapidly translocate to the nucleus and interact with specific regulatory elements to induce target gene transcription. STAT family members and chromosomal localizationSTAT proteins were originally discovered in interferon (IFN)-regulated gene transcription in the early 1990s. [10][11][12] Since then, a number of cytokines have been recognized to activate various STAT proteins (Table 1). Seven members of the STAT family of transcription factors have been identified in mammalian cells: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6.Convincing evidence from genetic mapping studies indicates a common ancestral origin that gave rise to 3 chromosomal clusters of STAT genes through a series of duplication processes (Table 2). 37 Structure of STATsPrevious characterization of the crystal structure of STAT molecules allowed a better understanding of the distinct functional domains within the STAT proteins. 38,39 Several domains are conserved in all STAT family members ( Figure 2; Table 3). STAT isoformsSTAT isoforms lacking regions of the c-terminal domain have a competitive dominant-negative (DN) effect on...

Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

“…In response to IL-7 signals, STAT5 regulates the survival and proliferation of B-cell progenitors and plays an important role in the generation of B-cell leukemia and lymphoma [36,42]. Notably, both BCR and IL-7 signals regulate the expression of Rag proteins via the PI3K/Akt/FoxO pathway and thus influence early B-cell development [43][44][45][46][47][48][49][50][51].…”

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

“…In fact, disruption of the mechanism leading to constitutive activation of STAT is considered to be a cancer-promoting factor (Benekli et al 2003).…”

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

“…Although Stat1-deficient mice do not display a heightened incidence of spontaneous neoplasms, they are more sensitive to chemical induction of tumors (Kaplan et al, 1998;Levy and Gilliland, 2000). However, STAT1 expression is frequently upregulated in tumors (Frank et al, 1997;Spiekermann et al, 2001;Widschwendter et al, 2002;Benekli et al, 2003;Hudelist et al, 2005) and associated with prosurvival functions under conditions of growth stress, such as X-irradiation (Khodarev et al, 2004), or anticancer therapy (Friedberg et al, 2004;Roberts et al, 2005). Even ectopic expression of IFNg can support tumor development via STAT1 activation (Wang et al, 2000;Lin et al, 2004).…”